CN112823025A - 用于通过抑制胞外体释放以治疗疾病的组成物及方法 - Google Patents
用于通过抑制胞外体释放以治疗疾病的组成物及方法 Download PDFInfo
- Publication number
- CN112823025A CN112823025A CN201880097355.3A CN201880097355A CN112823025A CN 112823025 A CN112823025 A CN 112823025A CN 201880097355 A CN201880097355 A CN 201880097355A CN 112823025 A CN112823025 A CN 112823025A
- Authority
- CN
- China
- Prior art keywords
- peptide
- cells
- seq
- cell
- peg
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 238000000034 method Methods 0.000 title claims abstract description 70
- 239000000203 mixture Substances 0.000 title description 44
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title description 16
- 201000010099 disease Diseases 0.000 title description 14
- 230000002401 inhibitory effect Effects 0.000 title description 9
- 108090000765 processed proteins & peptides Proteins 0.000 claims abstract description 402
- 238000011282 treatment Methods 0.000 claims abstract description 61
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 42
- 108010051109 Cell-Penetrating Peptides Proteins 0.000 claims abstract description 39
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 36
- 102000020313 Cell-Penetrating Peptides Human genes 0.000 claims abstract description 33
- 239000002246 antineoplastic agent Substances 0.000 claims abstract description 30
- 201000011510 cancer Diseases 0.000 claims abstract description 29
- 230000004048 modification Effects 0.000 claims abstract description 19
- 238000012986 modification Methods 0.000 claims abstract description 19
- 108090000197 Clusterin Proteins 0.000 claims abstract description 18
- 102000003780 Clusterin Human genes 0.000 claims abstract description 18
- 230000027455 binding Effects 0.000 claims abstract description 13
- 230000003248 secreting effect Effects 0.000 claims abstract description 13
- 210000004027 cell Anatomy 0.000 claims description 380
- 108090000623 proteins and genes Proteins 0.000 claims description 139
- 102000004169 proteins and genes Human genes 0.000 claims description 135
- 231100000518 lethal Toxicity 0.000 claims description 100
- 230000001665 lethal effect Effects 0.000 claims description 100
- 206010006187 Breast cancer Diseases 0.000 claims description 79
- 208000026310 Breast neoplasm Diseases 0.000 claims description 79
- 208000032839 leukemia Diseases 0.000 claims description 54
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 claims description 49
- 229930012538 Paclitaxel Natural products 0.000 claims description 48
- 229960001592 paclitaxel Drugs 0.000 claims description 48
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 claims description 47
- 239000003112 inhibitor Substances 0.000 claims description 47
- 229960004316 cisplatin Drugs 0.000 claims description 46
- SUBDBMMJDZJVOS-UHFFFAOYSA-N 5-methoxy-2-{[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]sulfinyl}-1H-benzimidazole Chemical compound N=1C2=CC(OC)=CC=C2NC=1S(=O)CC1=NC=C(C)C(OC)=C1C SUBDBMMJDZJVOS-UHFFFAOYSA-N 0.000 claims description 38
- VSKYOTRJSLYFHX-UXJRWBAGSA-M (2z,5e)-3-ethyl-2-[(1-ethylpyridin-1-ium-2-yl)methylidene]-5-(3-methyl-1,3-benzothiazol-2-ylidene)-1,3-thiazolidin-4-one;chloride Chemical group [Cl-].S1\C(=C\2N(C3=CC=CC=C3S/2)C)C(=O)N(CC)\C1=C\C1=CC=CC=[N+]1CC VSKYOTRJSLYFHX-UXJRWBAGSA-M 0.000 claims description 37
- 229960000381 omeprazole Drugs 0.000 claims description 37
- 239000013604 expression vector Substances 0.000 claims description 25
- 239000002105 nanoparticle Substances 0.000 claims description 25
- 239000003795 chemical substances by application Substances 0.000 claims description 19
- 239000003814 drug Substances 0.000 claims description 19
- 108091033319 polynucleotide Proteins 0.000 claims description 19
- 102000040430 polynucleotide Human genes 0.000 claims description 19
- 239000002157 polynucleotide Substances 0.000 claims description 19
- 229940121649 protein inhibitor Drugs 0.000 claims description 19
- 239000012268 protein inhibitor Substances 0.000 claims description 19
- 229940079593 drug Drugs 0.000 claims description 17
- 230000001105 regulatory effect Effects 0.000 claims description 17
- 102000012338 Poly(ADP-ribose) Polymerases Human genes 0.000 claims description 11
- 108010061844 Poly(ADP-ribose) Polymerases Proteins 0.000 claims description 11
- 229920000776 Poly(Adenosine diphosphate-ribose) polymerase Polymers 0.000 claims description 11
- 230000037361 pathway Effects 0.000 claims description 10
- RXMUPNVSYKGKMY-UHFFFAOYSA-N 3-amino-6-chloro-n-(diaminomethylidene)-5-(dimethylamino)pyrazine-2-carboxamide Chemical compound CN(C)C1=NC(N)=C(C(=O)N=C(N)N)N=C1Cl RXMUPNVSYKGKMY-UHFFFAOYSA-N 0.000 claims description 9
- 239000003937 drug carrier Substances 0.000 claims description 9
- 108010050904 Interferons Proteins 0.000 claims description 7
- 102000014150 Interferons Human genes 0.000 claims description 7
- 102100022760 Stress-70 protein, mitochondrial Human genes 0.000 claims description 7
- 229940125497 HER2 kinase inhibitor Drugs 0.000 claims description 6
- 101001059454 Homo sapiens Serine/threonine-protein kinase MARK2 Proteins 0.000 claims description 6
- 108091054455 MAP kinase family Proteins 0.000 claims description 6
- 102000043136 MAP kinase family Human genes 0.000 claims description 6
- 229940079156 Proteasome inhibitor Drugs 0.000 claims description 6
- 102100028904 Serine/threonine-protein kinase MARK2 Human genes 0.000 claims description 6
- 229940123237 Taxane Drugs 0.000 claims description 6
- 229940124304 VEGF/VEGFR inhibitor Drugs 0.000 claims description 6
- 229940100198 alkylating agent Drugs 0.000 claims description 6
- 239000002168 alkylating agent Substances 0.000 claims description 6
- 239000003817 anthracycline antibiotic agent Substances 0.000 claims description 6
- 230000000340 anti-metabolite Effects 0.000 claims description 6
- 239000000729 antidote Substances 0.000 claims description 6
- 239000013059 antihormonal agent Substances 0.000 claims description 6
- 229940100197 antimetabolite Drugs 0.000 claims description 6
- 239000002256 antimetabolite Substances 0.000 claims description 6
- 229940121647 egfr inhibitor Drugs 0.000 claims description 6
- 239000003276 histone deacetylase inhibitor Substances 0.000 claims description 6
- 229940121372 histone deacetylase inhibitor Drugs 0.000 claims description 6
- 230000003054 hormonal effect Effects 0.000 claims description 6
- 229940043355 kinase inhibitor Drugs 0.000 claims description 6
- 229940124303 multikinase inhibitor Drugs 0.000 claims description 6
- 239000003757 phosphotransferase inhibitor Substances 0.000 claims description 6
- 239000003207 proteasome inhibitor Substances 0.000 claims description 6
- 239000003197 protein kinase B inhibitor Substances 0.000 claims description 6
- ZAHRKKWIAAJSAO-UHFFFAOYSA-N rapamycin Natural products COCC(O)C(=C/C(C)C(=O)CC(OC(=O)C1CCCCN1C(=O)C(=O)C2(O)OC(CC(OC)C(=CC=CC=CC(C)CC(C)C(=O)C)C)CCC2C)C(C)CC3CCC(O)C(C3)OC)C ZAHRKKWIAAJSAO-UHFFFAOYSA-N 0.000 claims description 6
- 229960002930 sirolimus Drugs 0.000 claims description 6
- QFJCIRLUMZQUOT-HPLJOQBZSA-N sirolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 QFJCIRLUMZQUOT-HPLJOQBZSA-N 0.000 claims description 6
- DKPFODGZWDEEBT-QFIAKTPHSA-N taxane Chemical class C([C@]1(C)CCC[C@@H](C)[C@H]1C1)C[C@H]2[C@H](C)CC[C@@H]1C2(C)C DKPFODGZWDEEBT-QFIAKTPHSA-N 0.000 claims description 6
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 claims description 6
- 239000005483 tyrosine kinase inhibitor Substances 0.000 claims description 6
- 101100507655 Canis lupus familiaris HSPA1 gene Proteins 0.000 claims description 5
- 108010065917 TOR Serine-Threonine Kinases Proteins 0.000 claims description 5
- 102000013530 TOR Serine-Threonine Kinases Human genes 0.000 claims description 5
- 101710183280 Topoisomerase Proteins 0.000 claims description 5
- 229940045799 anthracyclines and related substance Drugs 0.000 claims description 5
- 239000003886 aromatase inhibitor Substances 0.000 claims description 5
- 229940046844 aromatase inhibitors Drugs 0.000 claims description 5
- 210000003793 centrosome Anatomy 0.000 claims description 5
- 239000002574 poison Substances 0.000 claims description 5
- 231100000614 poison Toxicity 0.000 claims description 5
- 229940043441 phosphoinositide 3-kinase inhibitor Drugs 0.000 claims description 4
- 229940126638 Akt inhibitor Drugs 0.000 claims description 3
- 229940121849 Mitotic inhibitor Drugs 0.000 claims description 3
- 229940079322 interferon Drugs 0.000 claims description 3
- 108010072187 mortalin Proteins 0.000 claims description 3
- 125000003275 alpha amino acid group Chemical group 0.000 claims 4
- 235000018102 proteins Nutrition 0.000 description 127
- 102000004196 processed proteins & peptides Human genes 0.000 description 108
- 210000001808 exosome Anatomy 0.000 description 94
- 229920001223 polyethylene glycol Polymers 0.000 description 64
- 239000002202 Polyethylene glycol Substances 0.000 description 53
- 201000009030 Carcinoma Diseases 0.000 description 48
- 230000000295 complement effect Effects 0.000 description 38
- 102000012440 Acetylcholinesterase Human genes 0.000 description 36
- 108010022752 Acetylcholinesterase Proteins 0.000 description 36
- 229940022698 acetylcholinesterase Drugs 0.000 description 36
- -1 cyclic lactam Chemical class 0.000 description 36
- 208000015474 Central precocious puberty Diseases 0.000 description 32
- 208000037064 Papilloma of choroid plexus Diseases 0.000 description 32
- 108020004459 Small interfering RNA Proteins 0.000 description 31
- 230000000694 effects Effects 0.000 description 30
- 238000004458 analytical method Methods 0.000 description 28
- 230000037396 body weight Effects 0.000 description 28
- 239000002245 particle Substances 0.000 description 28
- 239000004055 small Interfering RNA Substances 0.000 description 28
- 150000001413 amino acids Chemical group 0.000 description 27
- 230000006907 apoptotic process Effects 0.000 description 27
- 238000002474 experimental method Methods 0.000 description 27
- 238000003556 assay Methods 0.000 description 23
- 230000001404 mediated effect Effects 0.000 description 22
- 238000001262 western blot Methods 0.000 description 21
- 206010039491 Sarcoma Diseases 0.000 description 20
- 230000002829 reductive effect Effects 0.000 description 20
- 125000006850 spacer group Chemical group 0.000 description 20
- 210000004899 c-terminal region Anatomy 0.000 description 17
- 238000009472 formulation Methods 0.000 description 17
- 239000013642 negative control Substances 0.000 description 17
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 16
- 235000001014 amino acid Nutrition 0.000 description 16
- 229940024606 amino acid Drugs 0.000 description 16
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 16
- 230000002438 mitochondrial effect Effects 0.000 description 16
- 239000002953 phosphate buffered saline Substances 0.000 description 16
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 15
- 230000008878 coupling Effects 0.000 description 15
- 238000010168 coupling process Methods 0.000 description 15
- 238000005859 coupling reaction Methods 0.000 description 15
- 230000028327 secretion Effects 0.000 description 15
- 239000000243 solution Substances 0.000 description 15
- 239000013598 vector Substances 0.000 description 15
- JBCLFWXMTIKCCB-UHFFFAOYSA-N H-Gly-Phe-OH Natural products NCC(=O)NC(C(O)=O)CC1=CC=CC=C1 JBCLFWXMTIKCCB-UHFFFAOYSA-N 0.000 description 14
- ZLAKUZDMKVKFAI-JYJNAYRXSA-N Phe-Pro-Val Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C(C)C)C(O)=O ZLAKUZDMKVKFAI-JYJNAYRXSA-N 0.000 description 14
- 230000001965 increasing effect Effects 0.000 description 14
- 238000013508 migration Methods 0.000 description 14
- DNIAPMSPPWPWGF-UHFFFAOYSA-N monopropylene glycol Natural products CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 14
- 230000035755 proliferation Effects 0.000 description 14
- 230000008685 targeting Effects 0.000 description 14
- 210000004881 tumor cell Anatomy 0.000 description 14
- 108010065472 Vimentin Proteins 0.000 description 13
- 102100035071 Vimentin Human genes 0.000 description 13
- 238000004113 cell culture Methods 0.000 description 13
- 238000003776 cleavage reaction Methods 0.000 description 13
- 238000002347 injection Methods 0.000 description 13
- 239000007924 injection Substances 0.000 description 13
- 201000001441 melanoma Diseases 0.000 description 13
- 239000012528 membrane Substances 0.000 description 13
- 230000005012 migration Effects 0.000 description 13
- 230000007017 scission Effects 0.000 description 13
- 210000005048 vimentin Anatomy 0.000 description 13
- 230000030833 cell death Effects 0.000 description 12
- 230000012292 cell migration Effects 0.000 description 12
- 231100000135 cytotoxicity Toxicity 0.000 description 12
- 230000003013 cytotoxicity Effects 0.000 description 12
- 210000002966 serum Anatomy 0.000 description 12
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 11
- 108091007960 PI3Ks Proteins 0.000 description 11
- 102000003993 Phosphatidylinositol 3-kinases Human genes 0.000 description 11
- 108090000430 Phosphatidylinositol 3-kinases Proteins 0.000 description 11
- 102100033344 Programmed cell death 6-interacting protein Human genes 0.000 description 11
- 210000001519 tissue Anatomy 0.000 description 11
- 208000035473 Communicable disease Diseases 0.000 description 10
- 101000836492 Dictyostelium discoideum ALG-2 interacting protein X Proteins 0.000 description 10
- 101001134621 Homo sapiens Programmed cell death 6-interacting protein Proteins 0.000 description 10
- 108010076504 Protein Sorting Signals Proteins 0.000 description 10
- 239000002253 acid Substances 0.000 description 10
- 230000002986 anti-lethal effect Effects 0.000 description 10
- 230000007423 decrease Effects 0.000 description 10
- 150000002148 esters Chemical class 0.000 description 10
- 238000005259 measurement Methods 0.000 description 10
- 239000002609 medium Substances 0.000 description 10
- 231100001221 nontumorigenic Toxicity 0.000 description 10
- 150000007523 nucleic acids Chemical class 0.000 description 10
- 229920001184 polypeptide Polymers 0.000 description 10
- 239000000523 sample Substances 0.000 description 10
- 239000002502 liposome Substances 0.000 description 9
- 229920000642 polymer Polymers 0.000 description 9
- 230000001225 therapeutic effect Effects 0.000 description 9
- 108020004414 DNA Proteins 0.000 description 8
- 125000000217 alkyl group Chemical group 0.000 description 8
- 150000001408 amides Chemical class 0.000 description 8
- 230000000903 blocking effect Effects 0.000 description 8
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 8
- 230000004663 cell proliferation Effects 0.000 description 8
- 238000000576 coating method Methods 0.000 description 8
- 150000001875 compounds Chemical class 0.000 description 8
- 239000012228 culture supernatant Substances 0.000 description 8
- 102000039446 nucleic acids Human genes 0.000 description 8
- 108020004707 nucleic acids Proteins 0.000 description 8
- 239000011780 sodium chloride Substances 0.000 description 8
- 239000000126 substance Substances 0.000 description 8
- 239000000758 substrate Substances 0.000 description 8
- 239000006228 supernatant Substances 0.000 description 8
- DZLNHFMRPBPULJ-UHFFFAOYSA-N thioproline Chemical compound OC(=O)C1CSCN1 DZLNHFMRPBPULJ-UHFFFAOYSA-N 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 102000030431 Asparaginyl endopeptidase Human genes 0.000 description 7
- 108091026890 Coding region Proteins 0.000 description 7
- 102000004190 Enzymes Human genes 0.000 description 7
- 108090000790 Enzymes Proteins 0.000 description 7
- 241000531123 GB virus C Species 0.000 description 7
- 241000725303 Human immunodeficiency virus Species 0.000 description 7
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 7
- 239000004698 Polyethylene Substances 0.000 description 7
- 150000001412 amines Chemical class 0.000 description 7
- 108010055066 asparaginylendopeptidase Proteins 0.000 description 7
- 239000000872 buffer Substances 0.000 description 7
- 210000000170 cell membrane Anatomy 0.000 description 7
- 229940088598 enzyme Drugs 0.000 description 7
- 108010081551 glycylphenylalanine Proteins 0.000 description 7
- 238000011534 incubation Methods 0.000 description 7
- 230000005764 inhibitory process Effects 0.000 description 7
- RGLRXNKKBLIBQS-XNHQSDQCSA-N leuprolide acetate Chemical compound CC(O)=O.CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)CC1=CC=C(O)C=C1 RGLRXNKKBLIBQS-XNHQSDQCSA-N 0.000 description 7
- 201000010879 mucinous adenocarcinoma Diseases 0.000 description 7
- 230000006320 pegylation Effects 0.000 description 7
- 239000011550 stock solution Substances 0.000 description 7
- 238000006467 substitution reaction Methods 0.000 description 7
- 239000004094 surface-active agent Substances 0.000 description 7
- 238000012384 transportation and delivery Methods 0.000 description 7
- KIUMMUBSPKGMOY-UHFFFAOYSA-N 3,3'-Dithiobis(6-nitrobenzoic acid) Chemical compound C1=C([N+]([O-])=O)C(C(=O)O)=CC(SSC=2C=C(C(=CC=2)[N+]([O-])=O)C(O)=O)=C1 KIUMMUBSPKGMOY-UHFFFAOYSA-N 0.000 description 6
- 241000283707 Capra Species 0.000 description 6
- 102000005593 Endopeptidases Human genes 0.000 description 6
- 108010059378 Endopeptidases Proteins 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 208000031886 HIV Infections Diseases 0.000 description 6
- 101000934368 Homo sapiens CD63 antigen Proteins 0.000 description 6
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 6
- 239000002147 L01XE04 - Sunitinib Substances 0.000 description 6
- 239000002136 L01XE07 - Lapatinib Substances 0.000 description 6
- 231100000002 MTT assay Toxicity 0.000 description 6
- 238000000134 MTT assay Methods 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 6
- XDKKMRPRRCOELJ-GUBZILKMSA-N Pro-Val-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](C(C)C)NC(=O)[C@@H]1CCCN1 XDKKMRPRRCOELJ-GUBZILKMSA-N 0.000 description 6
- 241000700605 Viruses Species 0.000 description 6
- 230000008901 benefit Effects 0.000 description 6
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 6
- 230000004709 cell invasion Effects 0.000 description 6
- 238000009826 distribution Methods 0.000 description 6
- 210000001163 endosome Anatomy 0.000 description 6
- 208000015181 infectious disease Diseases 0.000 description 6
- BCFGMOOMADDAQU-UHFFFAOYSA-N lapatinib Chemical compound O1C(CNCCS(=O)(=O)C)=CC=C1C1=CC=C(N=CN=C2NC=3C=C(Cl)C(OCC=4C=C(F)C=CC=4)=CC=3)C2=C1 BCFGMOOMADDAQU-UHFFFAOYSA-N 0.000 description 6
- 239000000463 material Substances 0.000 description 6
- 208000025113 myeloid leukemia Diseases 0.000 description 6
- 229960001972 panitumumab Drugs 0.000 description 6
- 230000009467 reduction Effects 0.000 description 6
- 229940126586 small molecule drug Drugs 0.000 description 6
- 239000013603 viral vector Substances 0.000 description 6
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 5
- RLMISHABBKUNFO-WHFBIAKZSA-N Ala-Ala-Gly Chemical compound C[C@H](N)C(=O)N[C@@H](C)C(=O)NCC(O)=O RLMISHABBKUNFO-WHFBIAKZSA-N 0.000 description 5
- VHAQSYHSDKERBS-XPUUQOCRSA-N Ala-Val-Gly Chemical compound C[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)NCC(O)=O VHAQSYHSDKERBS-XPUUQOCRSA-N 0.000 description 5
- 108010034753 Complement Membrane Attack Complex Proteins 0.000 description 5
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 description 5
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 5
- 241000713772 Human immunodeficiency virus 1 Species 0.000 description 5
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 5
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 5
- 206010025323 Lymphomas Diseases 0.000 description 5
- GNLJXWBNLAIPEP-MELADBBJSA-N Lys-His-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC2=CN=CN2)NC(=O)[C@H](CCCCN)N)C(=O)O GNLJXWBNLAIPEP-MELADBBJSA-N 0.000 description 5
- 229920001213 Polysorbate 20 Polymers 0.000 description 5
- 239000004372 Polyvinyl alcohol Substances 0.000 description 5
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 5
- QRCBQDPRKMYTMB-IHPCNDPISA-N Tyr-Trp-Ser Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CO)C(=O)O)NC(=O)[C@H](CC3=CC=C(C=C3)O)N QRCBQDPRKMYTMB-IHPCNDPISA-N 0.000 description 5
- 239000013543 active substance Substances 0.000 description 5
- 230000008499 blood brain barrier function Effects 0.000 description 5
- 210000001218 blood-brain barrier Anatomy 0.000 description 5
- 210000000481 breast Anatomy 0.000 description 5
- 239000000969 carrier Substances 0.000 description 5
- 230000010261 cell growth Effects 0.000 description 5
- 230000008859 change Effects 0.000 description 5
- 230000003247 decreasing effect Effects 0.000 description 5
- 238000001514 detection method Methods 0.000 description 5
- 239000002552 dosage form Substances 0.000 description 5
- 238000005516 engineering process Methods 0.000 description 5
- 210000001723 extracellular space Anatomy 0.000 description 5
- 125000000524 functional group Chemical group 0.000 description 5
- 238000003384 imaging method Methods 0.000 description 5
- 238000002955 isolation Methods 0.000 description 5
- 239000003446 ligand Substances 0.000 description 5
- 125000005647 linker group Chemical group 0.000 description 5
- 208000003747 lymphoid leukemia Diseases 0.000 description 5
- 230000003211 malignant effect Effects 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 239000011159 matrix material Substances 0.000 description 5
- 229910052751 metal Inorganic materials 0.000 description 5
- 239000002184 metal Substances 0.000 description 5
- 229910044991 metal oxide Inorganic materials 0.000 description 5
- 150000004706 metal oxides Chemical class 0.000 description 5
- 238000010232 migration assay Methods 0.000 description 5
- 239000002773 nucleotide Substances 0.000 description 5
- 125000003729 nucleotide group Chemical group 0.000 description 5
- 230000003204 osmotic effect Effects 0.000 description 5
- 238000007911 parenteral administration Methods 0.000 description 5
- 239000008188 pellet Substances 0.000 description 5
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 5
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 5
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 5
- 229920002451 polyvinyl alcohol Polymers 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- 230000008569 process Effects 0.000 description 5
- 230000035945 sensitivity Effects 0.000 description 5
- 235000004400 serine Nutrition 0.000 description 5
- 150000003384 small molecules Chemical class 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- QMOQBVOBWVNSNO-UHFFFAOYSA-N 2-[[2-[[2-[(2-azaniumylacetyl)amino]acetyl]amino]acetyl]amino]acetate Chemical compound NCC(=O)NCC(=O)NCC(=O)NCC(O)=O QMOQBVOBWVNSNO-UHFFFAOYSA-N 0.000 description 4
- 108010088751 Albumins Proteins 0.000 description 4
- 102000009027 Albumins Human genes 0.000 description 4
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 4
- 241000894006 Bacteria Species 0.000 description 4
- 230000005653 Brownian motion process Effects 0.000 description 4
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 4
- 102100025222 CD63 antigen Human genes 0.000 description 4
- DLGOEMSEDOSKAD-UHFFFAOYSA-N Carmustine Chemical compound ClCCNC(=O)N(N=O)CCCl DLGOEMSEDOSKAD-UHFFFAOYSA-N 0.000 description 4
- 102000014914 Carrier Proteins Human genes 0.000 description 4
- 229920002307 Dextran Polymers 0.000 description 4
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 4
- 108010010803 Gelatin Proteins 0.000 description 4
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 4
- 239000004471 Glycine Substances 0.000 description 4
- VCBWXASUBZIFLQ-IHRRRGAJSA-N His-Pro-Leu Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(C)C)C(O)=O VCBWXASUBZIFLQ-IHRRRGAJSA-N 0.000 description 4
- 208000010747 Hodgkins lymphoma Diseases 0.000 description 4
- 101000903318 Homo sapiens Stress-70 protein, mitochondrial Proteins 0.000 description 4
- 241000713340 Human immunodeficiency virus 2 Species 0.000 description 4
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 4
- SHGAZHPCJJPHSC-NUEINMDLSA-N Isotretinoin Chemical compound OC(=O)C=C(C)/C=C/C=C(C)C=CC1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-NUEINMDLSA-N 0.000 description 4
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 4
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 4
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 4
- 108010000817 Leuprolide Proteins 0.000 description 4
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 4
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 description 4
- 108091028043 Nucleic acid sequence Proteins 0.000 description 4
- 102000007981 Ornithine carbamoyltransferase Human genes 0.000 description 4
- 241000283973 Oryctolagus cuniculus Species 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- 239000012980 RPMI-1640 medium Substances 0.000 description 4
- NKANXQFJJICGDU-QPLCGJKRSA-N Tamoxifen Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 NKANXQFJJICGDU-QPLCGJKRSA-N 0.000 description 4
- MDYSKHBSPXUOPV-JSGCOSHPSA-N Val-Gly-Phe Chemical compound CC(C)[C@@H](C(=O)NCC(=O)N[C@@H](CC1=CC=CC=C1)C(=O)O)N MDYSKHBSPXUOPV-JSGCOSHPSA-N 0.000 description 4
- 230000021736 acetylation Effects 0.000 description 4
- 238000006640 acetylation reaction Methods 0.000 description 4
- 125000003277 amino group Chemical group 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 235000009697 arginine Nutrition 0.000 description 4
- 230000004888 barrier function Effects 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 108091008324 binding proteins Proteins 0.000 description 4
- 210000004556 brain Anatomy 0.000 description 4
- 238000005537 brownian motion Methods 0.000 description 4
- 239000006172 buffering agent Substances 0.000 description 4
- 229910002092 carbon dioxide Inorganic materials 0.000 description 4
- 229920001577 copolymer Polymers 0.000 description 4
- UFULAYFCSOUIOV-UHFFFAOYSA-N cysteamine Chemical group NCCS UFULAYFCSOUIOV-UHFFFAOYSA-N 0.000 description 4
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 4
- 235000018417 cysteine Nutrition 0.000 description 4
- 125000000151 cysteine group Chemical group N[C@@H](CS)C(=O)* 0.000 description 4
- 230000001086 cytosolic effect Effects 0.000 description 4
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 description 4
- 238000009792 diffusion process Methods 0.000 description 4
- 239000006185 dispersion Substances 0.000 description 4
- 231100000673 dose–response relationship Toxicity 0.000 description 4
- 210000002472 endoplasmic reticulum Anatomy 0.000 description 4
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 4
- 230000005284 excitation Effects 0.000 description 4
- 230000006870 function Effects 0.000 description 4
- 239000000499 gel Substances 0.000 description 4
- 229920000159 gelatin Polymers 0.000 description 4
- 239000008273 gelatin Substances 0.000 description 4
- 235000019322 gelatine Nutrition 0.000 description 4
- 235000011852 gelatine desserts Nutrition 0.000 description 4
- 229960003297 gemtuzumab ozogamicin Drugs 0.000 description 4
- 235000011187 glycerol Nutrition 0.000 description 4
- 108010001064 glycyl-glycyl-glycyl-glycine Proteins 0.000 description 4
- 230000012010 growth Effects 0.000 description 4
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 4
- 235000014304 histidine Nutrition 0.000 description 4
- 239000004615 ingredient Substances 0.000 description 4
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 4
- 230000003993 interaction Effects 0.000 description 4
- 229940047124 interferons Drugs 0.000 description 4
- ATHLLZUXVPNPAW-UHFFFAOYSA-N lamellarin d Chemical compound C1=C(O)C(OC)=CC(C2=C3C4=CC(OC)=C(O)C=C4C=CN3C3=C2C=2C=C(OC)C(O)=CC=2OC3=O)=C1 ATHLLZUXVPNPAW-UHFFFAOYSA-N 0.000 description 4
- 210000003712 lysosome Anatomy 0.000 description 4
- 230000001868 lysosomic effect Effects 0.000 description 4
- 239000000546 pharmaceutical excipient Substances 0.000 description 4
- 210000002706 plastid Anatomy 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 239000002243 precursor Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 229960004641 rituximab Drugs 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 4
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 206010041823 squamous cell carcinoma Diseases 0.000 description 4
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 4
- 230000004083 survival effect Effects 0.000 description 4
- 208000024891 symptom Diseases 0.000 description 4
- 238000001890 transfection Methods 0.000 description 4
- 238000012546 transfer Methods 0.000 description 4
- 239000012224 working solution Substances 0.000 description 4
- RTQWWZBSTRGEAV-PKHIMPSTSA-N 2-[[(2s)-2-[bis(carboxymethyl)amino]-3-[4-(methylcarbamoylamino)phenyl]propyl]-[2-[bis(carboxymethyl)amino]propyl]amino]acetic acid Chemical compound CNC(=O)NC1=CC=C(C[C@@H](CN(CC(C)N(CC(O)=O)CC(O)=O)CC(O)=O)N(CC(O)=O)CC(O)=O)C=C1 RTQWWZBSTRGEAV-PKHIMPSTSA-N 0.000 description 3
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 description 3
- QHASENCZLDHBGX-ONGXEEELSA-N Ala-Gly-Phe Chemical compound C[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 QHASENCZLDHBGX-ONGXEEELSA-N 0.000 description 3
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 3
- 239000004475 Arginine Substances 0.000 description 3
- MLDQJTXFUGDVEO-UHFFFAOYSA-N BAY-43-9006 Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=CC(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 MLDQJTXFUGDVEO-UHFFFAOYSA-N 0.000 description 3
- 206010004146 Basal cell carcinoma Diseases 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 3
- 208000006332 Choriocarcinoma Diseases 0.000 description 3
- PTOAARAWEBMLNO-KVQBGUIXSA-N Cladribine Chemical compound C1=NC=2C(N)=NC(Cl)=NC=2N1[C@H]1C[C@H](O)[C@@H](CO)O1 PTOAARAWEBMLNO-KVQBGUIXSA-N 0.000 description 3
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 3
- 102000000634 Cytochrome c oxidase subunit IV Human genes 0.000 description 3
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 3
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 3
- 150000008574 D-amino acids Chemical group 0.000 description 3
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 3
- 108010092160 Dactinomycin Proteins 0.000 description 3
- ZBNZXTGUTAYRHI-UHFFFAOYSA-N Dasatinib Chemical compound C=1C(N2CCN(CCO)CC2)=NC(C)=NC=1NC(S1)=NC=C1C(=O)NC1=C(C)C=CC=C1Cl ZBNZXTGUTAYRHI-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 108010016626 Dipeptides Proteins 0.000 description 3
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 3
- 108010040476 FITC-annexin A5 Proteins 0.000 description 3
- 241000233866 Fungi Species 0.000 description 3
- 108090001126 Furin Proteins 0.000 description 3
- 102000004961 Furin Human genes 0.000 description 3
- KFMBRBPXHVMDFN-UWVGGRQHSA-N Gly-Arg-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)CN)CCCNC(N)=N KFMBRBPXHVMDFN-UWVGGRQHSA-N 0.000 description 3
- 241000724675 Hepatitis E virus Species 0.000 description 3
- 208000017604 Hodgkin disease Diseases 0.000 description 3
- 208000021519 Hodgkin lymphoma Diseases 0.000 description 3
- XDXDZDZNSLXDNA-TZNDIEGXSA-N Idarubicin Chemical compound C1[C@H](N)[C@H](O)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2C[C@@](O)(C(C)=O)C1 XDXDZDZNSLXDNA-TZNDIEGXSA-N 0.000 description 3
- 102100040018 Interferon alpha-2 Human genes 0.000 description 3
- 108010078049 Interferon alpha-2 Proteins 0.000 description 3
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 3
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 3
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 3
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 3
- 239000004472 Lysine Substances 0.000 description 3
- 229930195725 Mannitol Natural products 0.000 description 3
- 108010000684 Matrix Metalloproteinases Proteins 0.000 description 3
- 102000002274 Matrix Metalloproteinases Human genes 0.000 description 3
- 206010027476 Metastases Diseases 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 description 3
- 108091061960 Naked DNA Proteins 0.000 description 3
- 101710198224 Ornithine carbamoyltransferase, mitochondrial Proteins 0.000 description 3
- 229920001734 PEG propionaldehyde Polymers 0.000 description 3
- 229910019142 PO4 Inorganic materials 0.000 description 3
- 229940083963 Peptide antagonist Drugs 0.000 description 3
- 102000003992 Peroxidases Human genes 0.000 description 3
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 3
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- 238000012288 TUNEL assay Methods 0.000 description 3
- KXFYAQUYJKOQMI-QEJZJMRPSA-N Trp-Ser-Gln Chemical compound C1=CC=C2C(C[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(O)=O)=CNC2=C1 KXFYAQUYJKOQMI-QEJZJMRPSA-N 0.000 description 3
- 108090000704 Tubulin Proteins 0.000 description 3
- 102000004243 Tubulin Human genes 0.000 description 3
- 208000036676 acute undifferentiated leukemia Diseases 0.000 description 3
- 239000000654 additive Substances 0.000 description 3
- 239000005557 antagonist Substances 0.000 description 3
- 239000003242 anti bacterial agent Substances 0.000 description 3
- 230000001093 anti-cancer Effects 0.000 description 3
- 229940075522 antidotes Drugs 0.000 description 3
- 239000000427 antigen Substances 0.000 description 3
- 108091007433 antigens Proteins 0.000 description 3
- 102000036639 antigens Human genes 0.000 description 3
- 239000003443 antiviral agent Substances 0.000 description 3
- 238000013459 approach Methods 0.000 description 3
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 3
- 108010029539 arginyl-prolyl-proline Proteins 0.000 description 3
- 229940120638 avastin Drugs 0.000 description 3
- 229960000397 bevacizumab Drugs 0.000 description 3
- 239000011230 binding agent Substances 0.000 description 3
- 229920002988 biodegradable polymer Polymers 0.000 description 3
- 239000004621 biodegradable polymer Substances 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 229940021260 by ache Drugs 0.000 description 3
- 230000022131 cell cycle Effects 0.000 description 3
- 230000025084 cell cycle arrest Effects 0.000 description 3
- 230000001413 cellular effect Effects 0.000 description 3
- 229960005395 cetuximab Drugs 0.000 description 3
- 238000012512 characterization method Methods 0.000 description 3
- 229960002436 cladribine Drugs 0.000 description 3
- 239000011248 coating agent Substances 0.000 description 3
- 230000004540 complement-dependent cytotoxicity Effects 0.000 description 3
- 210000004748 cultured cell Anatomy 0.000 description 3
- 238000012258 culturing Methods 0.000 description 3
- 229960000684 cytarabine Drugs 0.000 description 3
- 210000000805 cytoplasm Anatomy 0.000 description 3
- 229940127089 cytotoxic agent Drugs 0.000 description 3
- 229960000975 daunorubicin Drugs 0.000 description 3
- 230000001419 dependent effect Effects 0.000 description 3
- 238000013461 design Methods 0.000 description 3
- 239000002612 dispersion medium Substances 0.000 description 3
- 239000003534 dna topoisomerase inhibitor Substances 0.000 description 3
- 230000002121 endocytic effect Effects 0.000 description 3
- 239000003623 enhancer Substances 0.000 description 3
- 210000002919 epithelial cell Anatomy 0.000 description 3
- 230000007705 epithelial mesenchymal transition Effects 0.000 description 3
- 229940082789 erbitux Drugs 0.000 description 3
- 210000003527 eukaryotic cell Anatomy 0.000 description 3
- 230000007717 exclusion Effects 0.000 description 3
- 239000012091 fetal bovine serum Substances 0.000 description 3
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 3
- 229910052737 gold Inorganic materials 0.000 description 3
- 239000010931 gold Substances 0.000 description 3
- 229940022353 herceptin Drugs 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- 229960001001 ibritumomab tiuxetan Drugs 0.000 description 3
- 229940099279 idamycin Drugs 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 230000001506 immunosuppresive effect Effects 0.000 description 3
- 239000007972 injectable composition Substances 0.000 description 3
- 238000001990 intravenous administration Methods 0.000 description 3
- 239000007951 isotonicity adjuster Substances 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 229960004891 lapatinib Drugs 0.000 description 3
- 229960004338 leuprorelin Drugs 0.000 description 3
- 230000000670 limiting effect Effects 0.000 description 3
- 150000002632 lipids Chemical class 0.000 description 3
- 239000000314 lubricant Substances 0.000 description 3
- 235000018977 lysine Nutrition 0.000 description 3
- 230000002132 lysosomal effect Effects 0.000 description 3
- 239000011572 manganese Substances 0.000 description 3
- 239000000594 mannitol Substances 0.000 description 3
- 235000010355 mannitol Nutrition 0.000 description 3
- 239000003550 marker Substances 0.000 description 3
- PSGAAPLEWMOORI-PEINSRQWSA-N medroxyprogesterone acetate Chemical compound C([C@@]12C)CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2CC[C@]2(C)[C@@](OC(C)=O)(C(C)=O)CC[C@H]21 PSGAAPLEWMOORI-PEINSRQWSA-N 0.000 description 3
- 239000002082 metal nanoparticle Substances 0.000 description 3
- 230000009401 metastasis Effects 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 108091070501 miRNA Proteins 0.000 description 3
- 244000005700 microbiome Species 0.000 description 3
- 230000000394 mitotic effect Effects 0.000 description 3
- 210000002487 multivesicular body Anatomy 0.000 description 3
- LBWFXVZLPYTWQI-IPOVEDGCSA-N n-[2-(diethylamino)ethyl]-5-[(z)-(5-fluoro-2-oxo-1h-indol-3-ylidene)methyl]-2,4-dimethyl-1h-pyrrole-3-carboxamide;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.CCN(CC)CCNC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C LBWFXVZLPYTWQI-IPOVEDGCSA-N 0.000 description 3
- 210000000056 organ Anatomy 0.000 description 3
- 108040007629 peroxidase activity proteins Proteins 0.000 description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 3
- 239000010452 phosphate Substances 0.000 description 3
- 239000013612 plasmid Substances 0.000 description 3
- 229910052697 platinum Inorganic materials 0.000 description 3
- 239000013641 positive control Substances 0.000 description 3
- 230000002062 proliferating effect Effects 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 238000007363 ring formation reaction Methods 0.000 description 3
- 239000003419 rna directed dna polymerase inhibitor Substances 0.000 description 3
- BTIHMVBBUGXLCJ-OAHLLOKOSA-N seliciclib Chemical compound C=12N=CN(C(C)C)C2=NC(N[C@@H](CO)CC)=NC=1NCC1=CC=CC=C1 BTIHMVBBUGXLCJ-OAHLLOKOSA-N 0.000 description 3
- 239000000600 sorbitol Substances 0.000 description 3
- 235000010356 sorbitol Nutrition 0.000 description 3
- 239000003381 stabilizer Substances 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 239000008107 starch Substances 0.000 description 3
- 238000007920 subcutaneous administration Methods 0.000 description 3
- 235000000346 sugar Nutrition 0.000 description 3
- 150000008163 sugars Chemical class 0.000 description 3
- WINHZLLDWRZWRT-ATVHPVEESA-N sunitinib Chemical compound CCN(CC)CCNC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C WINHZLLDWRZWRT-ATVHPVEESA-N 0.000 description 3
- 229960001796 sunitinib Drugs 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 229940034785 sutent Drugs 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- 125000003396 thiol group Chemical group [H]S* 0.000 description 3
- 150000003573 thiols Chemical class 0.000 description 3
- 229940044693 topoisomerase inhibitor Drugs 0.000 description 3
- 229960005267 tositumomab Drugs 0.000 description 3
- 229960000575 trastuzumab Drugs 0.000 description 3
- 230000004614 tumor growth Effects 0.000 description 3
- 229940094060 tykerb Drugs 0.000 description 3
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 3
- 235000002374 tyrosine Nutrition 0.000 description 3
- 229960004528 vincristine Drugs 0.000 description 3
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 3
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 3
- 229920003169 water-soluble polymer Polymers 0.000 description 3
- AKNNEGZIBPJZJG-MSOLQXFVSA-N (-)-noscapine Chemical compound CN1CCC2=CC=3OCOC=3C(OC)=C2[C@@H]1[C@@H]1C2=CC=C(OC)C(OC)=C2C(=O)O1 AKNNEGZIBPJZJG-MSOLQXFVSA-N 0.000 description 2
- ZBVJFYPGLGEMIN-OYLNGHKZSA-N (2s)-n-[(2s)-1-[[(2s)-1-[[(2s)-1-[[(2s)-1-[[(2r)-1-[[(2s)-1-[[(2s)-1-[(2s)-2-[(2-amino-2-oxoethyl)carbamoyl]pyrrolidin-1-yl]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-(1h-indol-3-yl)-1-oxopropan-2-yl]amino]-3-( Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1.C([C@@H](C(=O)N[C@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)NCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 ZBVJFYPGLGEMIN-OYLNGHKZSA-N 0.000 description 2
- LJRDOKAZOAKLDU-UDXJMMFXSA-N (2s,3s,4r,5r,6r)-5-amino-2-(aminomethyl)-6-[(2r,3s,4r,5s)-5-[(1r,2r,3s,5r,6s)-3,5-diamino-2-[(2s,3r,4r,5s,6r)-3-amino-4,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-6-hydroxycyclohexyl]oxy-4-hydroxy-2-(hydroxymethyl)oxolan-3-yl]oxyoxane-3,4-diol;sulfuric ac Chemical compound OS(O)(=O)=O.N[C@@H]1[C@@H](O)[C@H](O)[C@H](CN)O[C@@H]1O[C@H]1[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](N)C[C@@H](N)[C@@H]2O)O[C@@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)N)O[C@@H]1CO LJRDOKAZOAKLDU-UDXJMMFXSA-N 0.000 description 2
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 2
- BTLXPCBPYBNQNR-UHFFFAOYSA-N 1-hydroxyanthraquinone Chemical compound O=C1C2=CC=CC=C2C(=O)C2=C1C=CC=C2O BTLXPCBPYBNQNR-UHFFFAOYSA-N 0.000 description 2
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- DGHHQBMTXTWTJV-BQAIUKQQSA-N 119413-54-6 Chemical compound Cl.C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 DGHHQBMTXTWTJV-BQAIUKQQSA-N 0.000 description 2
- UEJJHQNACJXSKW-UHFFFAOYSA-N 2-(2,6-dioxopiperidin-3-yl)-1H-isoindole-1,3(2H)-dione Chemical compound O=C1C2=CC=CC=C2C(=O)N1C1CCC(=O)NC1=O UEJJHQNACJXSKW-UHFFFAOYSA-N 0.000 description 2
- FUOOLUPWFVMBKG-UHFFFAOYSA-N 2-Aminoisobutyric acid Chemical compound CC(C)(N)C(O)=O FUOOLUPWFVMBKG-UHFFFAOYSA-N 0.000 description 2
- IUVCFHHAEHNCFT-INIZCTEOSA-N 2-[(1s)-1-[4-amino-3-(3-fluoro-4-propan-2-yloxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]ethyl]-6-fluoro-3-(3-fluorophenyl)chromen-4-one Chemical compound C1=C(F)C(OC(C)C)=CC=C1C(C1=C(N)N=CN=C11)=NN1[C@@H](C)C1=C(C=2C=C(F)C=CC=2)C(=O)C2=CC(F)=CC=C2O1 IUVCFHHAEHNCFT-INIZCTEOSA-N 0.000 description 2
- NTBLZMAMTZXLBP-UHFFFAOYSA-M 2-acetylsulfanylethyl(trimethyl)azanium;iodide Chemical compound [I-].CC(=O)SCC[N+](C)(C)C NTBLZMAMTZXLBP-UHFFFAOYSA-M 0.000 description 2
- IZHVBANLECCAGF-UHFFFAOYSA-N 2-hydroxy-3-(octadecanoyloxy)propyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)COC(=O)CCCCCCCCCCCCCCCCC IZHVBANLECCAGF-UHFFFAOYSA-N 0.000 description 2
- OWSRLHPWDZOHCR-UHFFFAOYSA-N 4,4-diaminobutanoic acid Chemical compound NC(N)CCC(O)=O OWSRLHPWDZOHCR-UHFFFAOYSA-N 0.000 description 2
- MDOJTZQKHMAPBK-UHFFFAOYSA-N 4-iodo-3-nitrobenzamide Chemical compound NC(=O)C1=CC=C(I)C([N+]([O-])=O)=C1 MDOJTZQKHMAPBK-UHFFFAOYSA-N 0.000 description 2
- XAUDJQYHKZQPEU-KVQBGUIXSA-N 5-aza-2'-deoxycytidine Chemical compound O=C1N=C(N)N=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 XAUDJQYHKZQPEU-KVQBGUIXSA-N 0.000 description 2
- WYWHKKSPHMUBEB-UHFFFAOYSA-N 6-Mercaptoguanine Natural products N1C(N)=NC(=S)C2=C1N=CN2 WYWHKKSPHMUBEB-UHFFFAOYSA-N 0.000 description 2
- 102100026802 72 kDa type IV collagenase Human genes 0.000 description 2
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 2
- 208000030507 AIDS Diseases 0.000 description 2
- 208000031261 Acute myeloid leukaemia Diseases 0.000 description 2
- 208000036762 Acute promyelocytic leukaemia Diseases 0.000 description 2
- 108700031308 Antennapedia Homeodomain Proteins 0.000 description 2
- XPSGESXVBSQZPL-SRVKXCTJSA-N Arg-Arg-Arg Chemical compound NC(N)=NCCC[C@H](N)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O XPSGESXVBSQZPL-SRVKXCTJSA-N 0.000 description 2
- MUXONAMCEUBVGA-DCAQKATOSA-N Arg-Arg-Gln Chemical compound NC(N)=NCCC[C@H](N)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CCC(N)=O)C(O)=O MUXONAMCEUBVGA-DCAQKATOSA-N 0.000 description 2
- GMFAGHNRXPSSJS-SRVKXCTJSA-N Arg-Leu-Gln Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O GMFAGHNRXPSSJS-SRVKXCTJSA-N 0.000 description 2
- BFYIZQONLCFLEV-DAELLWKTSA-N Aromasine Chemical compound O=C1C=C[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CC(=C)C2=C1 BFYIZQONLCFLEV-DAELLWKTSA-N 0.000 description 2
- HZPSDHRYYIORKR-WHFBIAKZSA-N Asn-Ala-Gly Chemical compound OC(=O)CNC(=O)[C@H](C)NC(=O)[C@@H](N)CC(N)=O HZPSDHRYYIORKR-WHFBIAKZSA-N 0.000 description 2
- ZAESWDKAMDVHLL-RCOVLWMOSA-N Asn-Val-Gly Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)NCC(O)=O ZAESWDKAMDVHLL-RCOVLWMOSA-N 0.000 description 2
- 102000015790 Asparaginase Human genes 0.000 description 2
- 108010024976 Asparaginase Proteins 0.000 description 2
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 description 2
- CWHUFRVAEUJCEF-UHFFFAOYSA-N BKM120 Chemical compound C1=NC(N)=CC(C(F)(F)F)=C1C1=CC(N2CCOCC2)=NC(N2CCOCC2)=N1 CWHUFRVAEUJCEF-UHFFFAOYSA-N 0.000 description 2
- 108010006654 Bleomycin Proteins 0.000 description 2
- 208000003174 Brain Neoplasms Diseases 0.000 description 2
- 239000004322 Butylated hydroxytoluene Substances 0.000 description 2
- NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 2
- 102000004225 Cathepsin B Human genes 0.000 description 2
- 108090000712 Cathepsin B Proteins 0.000 description 2
- 229910052684 Cerium Inorganic materials 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 2
- 241000711573 Coronaviridae Species 0.000 description 2
- 241000150230 Crimean-Congo hemorrhagic fever orthonairovirus Species 0.000 description 2
- 108010069514 Cyclic Peptides Proteins 0.000 description 2
- 102000001189 Cyclic Peptides Human genes 0.000 description 2
- 241000725619 Dengue virus Species 0.000 description 2
- 241001115402 Ebolavirus Species 0.000 description 2
- 102100038132 Endogenous retrovirus group K member 6 Pro protein Human genes 0.000 description 2
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 2
- HKVAMNSJSFKALM-GKUWKFKPSA-N Everolimus Chemical compound C1C[C@@H](OCCO)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 HKVAMNSJSFKALM-GKUWKFKPSA-N 0.000 description 2
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 2
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 2
- 108010074860 Factor Xa Proteins 0.000 description 2
- 208000008999 Giant Cell Carcinoma Diseases 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- JLXVRFDTDUGQEE-YFKPBYRVSA-N Gly-Arg Chemical group NCC(=O)N[C@H](C(O)=O)CCCN=C(N)N JLXVRFDTDUGQEE-YFKPBYRVSA-N 0.000 description 2
- BLCLNMBMMGCOAS-URPVMXJPSA-N Goserelin Chemical compound C([C@@H](C(=O)N[C@H](COC(C)(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N1[C@@H](CCC1)C(=O)NNC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 BLCLNMBMMGCOAS-URPVMXJPSA-N 0.000 description 2
- 108010069236 Goserelin Proteins 0.000 description 2
- 241000711549 Hepacivirus C Species 0.000 description 2
- 208000037262 Hepatitis delta Diseases 0.000 description 2
- 241000724709 Hepatitis delta virus Species 0.000 description 2
- 241000709721 Hepatovirus A Species 0.000 description 2
- 241000238631 Hexapoda Species 0.000 description 2
- CHIAUHSHDARFBD-ULQDDVLXSA-N His-Pro-Tyr Chemical compound C([C@H](N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(O)=O)C1=CN=CN1 CHIAUHSHDARFBD-ULQDDVLXSA-N 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- 101000627872 Homo sapiens 72 kDa type IV collagenase Proteins 0.000 description 2
- 101000990912 Homo sapiens Matrilysin Proteins 0.000 description 2
- 101000990902 Homo sapiens Matrix metalloproteinase-9 Proteins 0.000 description 2
- 241000701041 Human betaherpesvirus 7 Species 0.000 description 2
- 241000701027 Human herpesvirus 6 Species 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- VSNHCAURESNICA-UHFFFAOYSA-N Hydroxyurea Chemical compound NC(=O)NO VSNHCAURESNICA-UHFFFAOYSA-N 0.000 description 2
- 206010053574 Immunoblastic lymphoma Diseases 0.000 description 2
- 108060003951 Immunoglobulin Proteins 0.000 description 2
- 206010061218 Inflammation Diseases 0.000 description 2
- 108090001061 Insulin Proteins 0.000 description 2
- 102000004877 Insulin Human genes 0.000 description 2
- 108010065920 Insulin Lispro Proteins 0.000 description 2
- UQSXHKLRYXJYBZ-UHFFFAOYSA-N Iron oxide Chemical compound [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 description 2
- FADYJNXDPBKVCA-UHFFFAOYSA-N L-Phenylalanyl-L-lysin Natural products NCCCCC(C(O)=O)NC(=O)C(N)CC1=CC=CC=C1 FADYJNXDPBKVCA-UHFFFAOYSA-N 0.000 description 2
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 2
- WZNJWVWKTVETCG-YFKPBYRVSA-N L-mimosine Chemical compound OC(=O)[C@@H](N)CN1C=CC(=O)C(O)=C1 WZNJWVWKTVETCG-YFKPBYRVSA-N 0.000 description 2
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 description 2
- 239000002067 L01XE06 - Dasatinib Substances 0.000 description 2
- 239000005536 L01XE08 - Nilotinib Substances 0.000 description 2
- 239000003798 L01XE11 - Pazopanib Substances 0.000 description 2
- GRZSCTXVCDUIPO-SRVKXCTJSA-N Leu-Arg-Gln Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(O)=O GRZSCTXVCDUIPO-SRVKXCTJSA-N 0.000 description 2
- AMSSKPUHBUQBOQ-SRVKXCTJSA-N Leu-Ser-Lys Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)O)N AMSSKPUHBUQBOQ-SRVKXCTJSA-N 0.000 description 2
- HLFSDGLLUJUHTE-SNVBAGLBSA-N Levamisole Chemical compound C1([C@H]2CN3CCSC3=N2)=CC=CC=C1 HLFSDGLLUJUHTE-SNVBAGLBSA-N 0.000 description 2
- 208000028018 Lymphocytic leukaemia Diseases 0.000 description 2
- 241001115401 Marburgvirus Species 0.000 description 2
- 102100030417 Matrilysin Human genes 0.000 description 2
- 102100030412 Matrix metalloproteinase-9 Human genes 0.000 description 2
- XOGTZOOQQBDUSI-UHFFFAOYSA-M Mesna Chemical compound [Na+].[O-]S(=O)(=O)CCS XOGTZOOQQBDUSI-UHFFFAOYSA-M 0.000 description 2
- DBXMFHGGHMXYHY-DCAQKATOSA-N Met-Leu-Ser Chemical compound CSCC[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(O)=O DBXMFHGGHMXYHY-DCAQKATOSA-N 0.000 description 2
- 102000029749 Microtubule Human genes 0.000 description 2
- 108091022875 Microtubule Proteins 0.000 description 2
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 description 2
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 description 2
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 2
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 description 2
- 208000034176 Neoplasms, Germ Cell and Embryonal Diseases 0.000 description 2
- 206010029260 Neuroblastoma Diseases 0.000 description 2
- 239000000020 Nitrocellulose Substances 0.000 description 2
- KYRVNWMVYQXFEU-UHFFFAOYSA-N Nocodazole Chemical compound C1=C2NC(NC(=O)OC)=NC2=CC=C1C(=O)C1=CC=CS1 KYRVNWMVYQXFEU-UHFFFAOYSA-N 0.000 description 2
- 241000150452 Orthohantavirus Species 0.000 description 2
- 206010061535 Ovarian neoplasm Diseases 0.000 description 2
- UYJZZVDLGDDTCL-UHFFFAOYSA-N PJ34 Chemical compound C1=CC=C2C3=CC(NC(=O)CN(C)C)=CC=C3NC(=O)C2=C1 UYJZZVDLGDDTCL-UHFFFAOYSA-N 0.000 description 2
- 229930182555 Penicillin Natural products 0.000 description 2
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 2
- 108091005804 Peptidases Proteins 0.000 description 2
- 206010057249 Phagocytosis Diseases 0.000 description 2
- FADYJNXDPBKVCA-STQMWFEESA-N Phe-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@@H](N)CC1=CC=CC=C1 FADYJNXDPBKVCA-STQMWFEESA-N 0.000 description 2
- RBRNEFJTEHPDSL-ACRUOGEOSA-N Phe-Phe-Lys Chemical compound C([C@@H](C(=O)N[C@@H](CCCCN)C(O)=O)NC(=O)[C@@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 RBRNEFJTEHPDSL-ACRUOGEOSA-N 0.000 description 2
- 108091000080 Phosphotransferase Proteins 0.000 description 2
- 229920002732 Polyanhydride Polymers 0.000 description 2
- 229920001710 Polyorthoester Polymers 0.000 description 2
- HFZNNDWPHBRNPV-KZVJFYERSA-N Pro-Ala-Thr Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O HFZNNDWPHBRNPV-KZVJFYERSA-N 0.000 description 2
- FKYKZHOKDOPHSA-DCAQKATOSA-N Pro-Leu-Ser Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(O)=O FKYKZHOKDOPHSA-DCAQKATOSA-N 0.000 description 2
- FYKUEXMZYFIZKA-DCAQKATOSA-N Pro-Pro-Gln Chemical compound [H]N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(N)=O)C(O)=O FYKUEXMZYFIZKA-DCAQKATOSA-N 0.000 description 2
- RJKFOVLPORLFTN-LEKSSAKUSA-N Progesterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 RJKFOVLPORLFTN-LEKSSAKUSA-N 0.000 description 2
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 2
- NBBJYMSMWIIQGU-UHFFFAOYSA-N Propionic aldehyde Chemical compound CCC=O NBBJYMSMWIIQGU-UHFFFAOYSA-N 0.000 description 2
- 108010007568 Protamines Proteins 0.000 description 2
- 102000007327 Protamines Human genes 0.000 description 2
- 239000004365 Protease Substances 0.000 description 2
- 102000055027 Protein Methyltransferases Human genes 0.000 description 2
- 108700040121 Protein Methyltransferases Proteins 0.000 description 2
- 241000713124 Rift Valley fever virus Species 0.000 description 2
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 2
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 2
- 229910052772 Samarium Inorganic materials 0.000 description 2
- UPLYXVPQLJVWMM-KKUMJFAQSA-N Ser-Phe-Leu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC(C)C)C(O)=O UPLYXVPQLJVWMM-KKUMJFAQSA-N 0.000 description 2
- 201000003176 Severe Acute Respiratory Syndrome Diseases 0.000 description 2
- BQCADISMDOOEFD-UHFFFAOYSA-N Silver Chemical compound [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 description 2
- 208000005718 Stomach Neoplasms Diseases 0.000 description 2
- 238000000692 Student's t-test Methods 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- NAVMQTYZDKMPEU-UHFFFAOYSA-N Targretin Chemical compound CC1=CC(C(CCC2(C)C)(C)C)=C2C=C1C(=C)C1=CC=C(C(O)=O)C=C1 NAVMQTYZDKMPEU-UHFFFAOYSA-N 0.000 description 2
- BPEGJWRSRHCHSN-UHFFFAOYSA-N Temozolomide Chemical compound O=C1N(C)N=NC2=C(C(N)=O)N=CN21 BPEGJWRSRHCHSN-UHFFFAOYSA-N 0.000 description 2
- MUMGGOZAMZWBJJ-DYKIIFRCSA-N Testostosterone Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 MUMGGOZAMZWBJJ-DYKIIFRCSA-N 0.000 description 2
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 2
- 239000004473 Threonine Substances 0.000 description 2
- 108090000190 Thrombin Proteins 0.000 description 2
- 208000002495 Uterine Neoplasms Diseases 0.000 description 2
- 241000251539 Vertebrata <Metazoa> Species 0.000 description 2
- 241000710886 West Nile virus Species 0.000 description 2
- 241000710772 Yellow fever virus Species 0.000 description 2
- XLOMVQKBTHCTTD-UHFFFAOYSA-N Zinc monoxide Chemical compound [Zn]=O XLOMVQKBTHCTTD-UHFFFAOYSA-N 0.000 description 2
- CBPNZQVSJQDFBE-SREVRWKESA-N [(1S,2R,4S)-4-[(2R)-2-[(1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32R,35R)-1,18-dihydroxy-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-2,3,10,14,20-pentaoxo-11,36-dioxa-4-azatricyclo[30.3.1.04,9]hexatriaconta-16,24,26,28-tetraen-12-yl]propyl]-2-methoxycyclohexyl] 3-hydroxy-2-(hydroxymethyl)-2-methylpropanoate Chemical compound C[C@@H]1CC[C@@H]2C[C@@H](/C(=C/C=C/C=C/[C@H](C[C@H](C(=O)[C@@H]([C@@H](/C(=C/[C@H](C(=O)C[C@H](OC(=O)[C@@H]3CCCCN3C(=O)C(=O)[C@@]1(O2)O)[C@H](C)C[C@@H]4CC[C@@H]([C@@H](C4)OC)OC(=O)C(C)(CO)CO)C)/C)O)OC)C)C)/C)OC CBPNZQVSJQDFBE-SREVRWKESA-N 0.000 description 2
- 108010023617 abarelix Proteins 0.000 description 2
- AIWRTTMUVOZGPW-HSPKUQOVSA-N abarelix Chemical compound C([C@@H](C(=O)N[C@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCNC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N[C@H](C)C(N)=O)N(C)C(=O)[C@H](CO)NC(=O)[C@@H](CC=1C=NC=CC=1)NC(=O)[C@@H](CC=1C=CC(Cl)=CC=1)NC(=O)[C@@H](CC=1C=C2C=CC=CC2=CC=1)NC(C)=O)C1=CC=C(O)C=C1 AIWRTTMUVOZGPW-HSPKUQOVSA-N 0.000 description 2
- 229960002184 abarelix Drugs 0.000 description 2
- GZOSMCIZMLWJML-VJLLXTKPSA-N abiraterone Chemical compound C([C@H]1[C@H]2[C@@H]([C@]3(CC[C@H](O)CC3=CC2)C)CC[C@@]11C)C=C1C1=CC=CN=C1 GZOSMCIZMLWJML-VJLLXTKPSA-N 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 150000001241 acetals Chemical class 0.000 description 2
- 108010052004 acetyl-2-naphthylalanyl-3-chlorophenylalanyl-1-oxohexadecyl-seryl-4-aminophenylalanyl(hydroorotyl)-4-aminophenylalanyl(carbamoyl)-leucyl-ILys-prolyl-alaninamide Proteins 0.000 description 2
- 229930183665 actinomycin Natural products 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- WOZSCQDILHKSGG-UHFFFAOYSA-N adefovir depivoxil Chemical compound N1=CN=C2N(CCOCP(=O)(OCOC(=O)C(C)(C)C)OCOC(=O)C(C)(C)C)C=NC2=C1N WOZSCQDILHKSGG-UHFFFAOYSA-N 0.000 description 2
- 208000009956 adenocarcinoma Diseases 0.000 description 2
- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 description 2
- 229960000548 alemtuzumab Drugs 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- QWCKQJZIFLGMSD-UHFFFAOYSA-N alpha-aminobutyric acid Chemical compound CCC(N)C(O)=O QWCKQJZIFLGMSD-UHFFFAOYSA-N 0.000 description 2
- 230000009435 amidation Effects 0.000 description 2
- 238000007112 amidation reaction Methods 0.000 description 2
- YBBLVLTVTVSKRW-UHFFFAOYSA-N anastrozole Chemical compound N#CC(C)(C)C1=CC(C(C)(C#N)C)=CC(CN2N=CN=C2)=C1 YBBLVLTVTVSKRW-UHFFFAOYSA-N 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 229940121375 antifungal agent Drugs 0.000 description 2
- 239000003429 antifungal agent Substances 0.000 description 2
- 125000000637 arginyl group Chemical group N[C@@H](CCCNC(N)=N)C(=O)* 0.000 description 2
- GOLCXWYRSKYTSP-UHFFFAOYSA-N arsenic trioxide Inorganic materials O1[As]2O[As]1O2 GOLCXWYRSKYTSP-UHFFFAOYSA-N 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 235000010323 ascorbic acid Nutrition 0.000 description 2
- 229960005070 ascorbic acid Drugs 0.000 description 2
- 239000011668 ascorbic acid Substances 0.000 description 2
- VSRXQHXAPYXROS-UHFFFAOYSA-N azanide;cyclobutane-1,1-dicarboxylic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OC(=O)C1(C(O)=O)CCC1 VSRXQHXAPYXROS-UHFFFAOYSA-N 0.000 description 2
- 230000001580 bacterial effect Effects 0.000 description 2
- 239000011324 bead Substances 0.000 description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 210000000601 blood cell Anatomy 0.000 description 2
- GXJABQQUPOEUTA-RDJZCZTQSA-N bortezomib Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)B(O)O)NC(=O)C=1N=CC=NC=1)C1=CC=CC=C1 GXJABQQUPOEUTA-RDJZCZTQSA-N 0.000 description 2
- 239000004067 bulking agent Substances 0.000 description 2
- 229950003628 buparlisib Drugs 0.000 description 2
- 229940112133 busulfex Drugs 0.000 description 2
- 235000010354 butylated hydroxytoluene Nutrition 0.000 description 2
- 229940095259 butylated hydroxytoluene Drugs 0.000 description 2
- 229940112129 campath Drugs 0.000 description 2
- 210000000234 capsid Anatomy 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 2
- 229960005243 carmustine Drugs 0.000 description 2
- 239000013592 cell lysate Substances 0.000 description 2
- 230000003833 cell viability Effects 0.000 description 2
- ZMIGMASIKSOYAM-UHFFFAOYSA-N cerium Chemical compound [Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce] ZMIGMASIKSOYAM-UHFFFAOYSA-N 0.000 description 2
- JCKYGMPEJWAADB-UHFFFAOYSA-N chlorambucil Chemical compound OC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 JCKYGMPEJWAADB-UHFFFAOYSA-N 0.000 description 2
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 2
- 229960002173 citrulline Drugs 0.000 description 2
- WDDPHFBMKLOVOX-AYQXTPAHSA-N clofarabine Chemical compound C1=NC=2C(N)=NC(Cl)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1F WDDPHFBMKLOVOX-AYQXTPAHSA-N 0.000 description 2
- 229910017052 cobalt Inorganic materials 0.000 description 2
- 239000010941 cobalt Substances 0.000 description 2
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 description 2
- 229960002271 cobimetinib Drugs 0.000 description 2
- 210000001072 colon Anatomy 0.000 description 2
- 238000002648 combination therapy Methods 0.000 description 2
- 239000000356 contaminant Substances 0.000 description 2
- 239000002577 cryoprotective agent Substances 0.000 description 2
- 208000035250 cutaneous malignant susceptibility to 1 melanoma Diseases 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- 238000002784 cytotoxicity assay Methods 0.000 description 2
- 231100000263 cytotoxicity test Toxicity 0.000 description 2
- 229960002448 dasatinib Drugs 0.000 description 2
- 230000034994 death Effects 0.000 description 2
- 231100000517 death Toxicity 0.000 description 2
- MEUCPCLKGZSHTA-XYAYPHGZSA-N degarelix Chemical compound C([C@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCNC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N[C@H](C)C(N)=O)NC(=O)[C@H](CC=1C=CC(NC(=O)[C@H]2NC(=O)NC(=O)C2)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@@H](CC=1C=NC=CC=1)NC(=O)[C@@H](CC=1C=CC(Cl)=CC=1)NC(=O)[C@@H](CC=1C=C2C=CC=CC2=CC=1)NC(C)=O)C1=CC=C(NC(N)=O)C=C1 MEUCPCLKGZSHTA-XYAYPHGZSA-N 0.000 description 2
- WHBIGIKBNXZKFE-UHFFFAOYSA-N delavirdine Chemical compound CC(C)NC1=CC=CN=C1N1CCN(C(=O)C=2NC3=CC=C(NS(C)(=O)=O)C=C3C=2)CC1 WHBIGIKBNXZKFE-UHFFFAOYSA-N 0.000 description 2
- 238000001212 derivatisation Methods 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- AUZONCFQVSMFAP-UHFFFAOYSA-N disulfiram Chemical compound CCN(CC)C(=S)SSC(=S)N(CC)CC AUZONCFQVSMFAP-UHFFFAOYSA-N 0.000 description 2
- 229960003668 docetaxel Drugs 0.000 description 2
- NOPFSRXAKWQILS-UHFFFAOYSA-N docosan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCCCCCO NOPFSRXAKWQILS-UHFFFAOYSA-N 0.000 description 2
- 229960004679 doxorubicin Drugs 0.000 description 2
- 241001493065 dsRNA viruses Species 0.000 description 2
- 230000008030 elimination Effects 0.000 description 2
- 238000003379 elimination reaction Methods 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- 238000009505 enteric coating Methods 0.000 description 2
- 239000002702 enteric coating Substances 0.000 description 2
- 229930013356 epothilone Natural products 0.000 description 2
- AAKJLRGGTJKAMG-UHFFFAOYSA-N erlotinib Chemical compound C=12C=C(OCCOC)C(OCCOC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 AAKJLRGGTJKAMG-UHFFFAOYSA-N 0.000 description 2
- 125000004185 ester group Chemical group 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 229960005420 etoposide Drugs 0.000 description 2
- 229960005167 everolimus Drugs 0.000 description 2
- 230000001747 exhibiting effect Effects 0.000 description 2
- 210000002744 extracellular matrix Anatomy 0.000 description 2
- 238000000684 flow cytometry Methods 0.000 description 2
- ODKNJVUHOIMIIZ-RRKCRQDMSA-N floxuridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ODKNJVUHOIMIIZ-RRKCRQDMSA-N 0.000 description 2
- 229960000961 floxuridine Drugs 0.000 description 2
- GIUYCYHIANZCFB-FJFJXFQQSA-N fludarabine phosphate Chemical compound C1=NC=2C(N)=NC(F)=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@@H]1O GIUYCYHIANZCFB-FJFJXFQQSA-N 0.000 description 2
- YLRFCQOZQXIBAB-RBZZARIASA-N fluoxymesterone Chemical group C1CC2=CC(=O)CC[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1CC[C@](C)(O)[C@@]1(C)C[C@@H]2O YLRFCQOZQXIBAB-RBZZARIASA-N 0.000 description 2
- 210000004211 gastric acid Anatomy 0.000 description 2
- 230000002496 gastric effect Effects 0.000 description 2
- XGALLCVXEZPNRQ-UHFFFAOYSA-N gefitinib Chemical compound C=12C=C(OCCCN3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 XGALLCVXEZPNRQ-UHFFFAOYSA-N 0.000 description 2
- 238000003197 gene knockdown Methods 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 235000013922 glutamic acid Nutrition 0.000 description 2
- 239000004220 glutamic acid Substances 0.000 description 2
- XKUKSGPZAADMRA-UHFFFAOYSA-N glycyl-glycyl-glycine Chemical compound NCC(=O)NCC(=O)NCC(O)=O XKUKSGPZAADMRA-UHFFFAOYSA-N 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 229920001519 homopolymer Polymers 0.000 description 2
- 102000057640 human CD63 Human genes 0.000 description 2
- 239000000017 hydrogel Substances 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 229960001330 hydroxycarbamide Drugs 0.000 description 2
- HOMGKSMUEGBAAB-UHFFFAOYSA-N ifosfamide Chemical compound ClCCNP1(=O)OCCCN1CCCl HOMGKSMUEGBAAB-UHFFFAOYSA-N 0.000 description 2
- 210000000987 immune system Anatomy 0.000 description 2
- 102000018358 immunoglobulin Human genes 0.000 description 2
- 230000001976 improved effect Effects 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 230000004054 inflammatory process Effects 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- 238000003780 insertion Methods 0.000 description 2
- 230000037431 insertion Effects 0.000 description 2
- 229940125396 insulin Drugs 0.000 description 2
- 238000001361 intraarterial administration Methods 0.000 description 2
- 230000003834 intracellular effect Effects 0.000 description 2
- 238000007913 intrathecal administration Methods 0.000 description 2
- 230000009545 invasion Effects 0.000 description 2
- GURKHSYORGJETM-WAQYZQTGSA-N irinotecan hydrochloride (anhydrous) Chemical compound Cl.C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 GURKHSYORGJETM-WAQYZQTGSA-N 0.000 description 2
- 229910052742 iron Inorganic materials 0.000 description 2
- 229960005280 isotretinoin Drugs 0.000 description 2
- HPJKCIUCZWXJDR-UHFFFAOYSA-N letrozole Chemical compound C1=CC(C#N)=CC=C1C(N1N=CN=C1)C1=CC=C(C#N)C=C1 HPJKCIUCZWXJDR-UHFFFAOYSA-N 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000007937 lozenge Substances 0.000 description 2
- 210000004072 lung Anatomy 0.000 description 2
- 201000000014 lung giant cell carcinoma Diseases 0.000 description 2
- 208000020816 lung neoplasm Diseases 0.000 description 2
- 229940087857 lupron Drugs 0.000 description 2
- 208000025036 lymphosarcoma Diseases 0.000 description 2
- 229920002521 macromolecule Polymers 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 210000004962 mammalian cell Anatomy 0.000 description 2
- SGDBTWWWUNNDEQ-LBPRGKRZSA-N melphalan Chemical compound OC(=O)[C@@H](N)CC1=CC=C(N(CCCl)CCCl)C=C1 SGDBTWWWUNNDEQ-LBPRGKRZSA-N 0.000 description 2
- 229960003151 mercaptamine Drugs 0.000 description 2
- 229960000485 methotrexate Drugs 0.000 description 2
- OSWPMRLSEDHDFF-UHFFFAOYSA-N methyl salicylate Chemical compound COC(=O)C1=CC=CC=C1O OSWPMRLSEDHDFF-UHFFFAOYSA-N 0.000 description 2
- 230000011987 methylation Effects 0.000 description 2
- 238000007069 methylation reaction Methods 0.000 description 2
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 2
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 2
- 239000003094 microcapsule Substances 0.000 description 2
- 210000004688 microtubule Anatomy 0.000 description 2
- 230000001617 migratory effect Effects 0.000 description 2
- 235000013336 milk Nutrition 0.000 description 2
- 239000008267 milk Substances 0.000 description 2
- 210000004080 milk Anatomy 0.000 description 2
- 229950002289 mimosine Drugs 0.000 description 2
- CFCUWKMKBJTWLW-BKHRDMLASA-N mithramycin Chemical compound O([C@@H]1C[C@@H](O[C@H](C)[C@H]1O)OC=1C=C2C=C3C[C@H]([C@@H](C(=O)C3=C(O)C2=C(O)C=1C)O[C@@H]1O[C@H](C)[C@@H](O)[C@H](O[C@@H]2O[C@H](C)[C@H](O)[C@H](O[C@@H]3O[C@H](C)[C@@H](O)[C@@](C)(O)C3)C2)C1)[C@H](OC)C(=O)[C@@H](O)[C@@H](C)O)[C@H]1C[C@@H](O)[C@H](O)[C@@H](C)O1 CFCUWKMKBJTWLW-BKHRDMLASA-N 0.000 description 2
- 210000003470 mitochondria Anatomy 0.000 description 2
- 229960004857 mitomycin Drugs 0.000 description 2
- KKZJGLLVHKMTCM-UHFFFAOYSA-N mitoxantrone Chemical compound O=C1C2=C(O)C=CC(O)=C2C(=O)C2=C1C(NCCNCCO)=CC=C2NCCNCCO KKZJGLLVHKMTCM-UHFFFAOYSA-N 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 2
- 239000007922 nasal spray Substances 0.000 description 2
- NQDJXKOVJZTUJA-UHFFFAOYSA-N nevirapine Chemical compound C12=NC=CC=C2C(=O)NC=2C(C)=CC=NC=2N1C1CC1 NQDJXKOVJZTUJA-UHFFFAOYSA-N 0.000 description 2
- 229910052759 nickel Inorganic materials 0.000 description 2
- HHZIURLSWUIHRB-UHFFFAOYSA-N nilotinib Chemical compound C1=NC(C)=CN1C1=CC(NC(=O)C=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)=CC(C(F)(F)F)=C1 HHZIURLSWUIHRB-UHFFFAOYSA-N 0.000 description 2
- XWXYUMMDTVBTOU-UHFFFAOYSA-N nilutamide Chemical compound O=C1C(C)(C)NC(=O)N1C1=CC=C([N+]([O-])=O)C(C(F)(F)F)=C1 XWXYUMMDTVBTOU-UHFFFAOYSA-N 0.000 description 2
- 229920001220 nitrocellulos Polymers 0.000 description 2
- 229950006344 nocodazole Drugs 0.000 description 2
- 231100001160 nonlethal Toxicity 0.000 description 2
- 230000000269 nucleophilic effect Effects 0.000 description 2
- 229960002450 ofatumumab Drugs 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
- 201000008968 osteosarcoma Diseases 0.000 description 2
- 229940127084 other anti-cancer agent Drugs 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- 244000045947 parasite Species 0.000 description 2
- 230000009054 pathological process Effects 0.000 description 2
- CUIHSIWYWATEQL-UHFFFAOYSA-N pazopanib Chemical compound C1=CC2=C(C)N(C)N=C2C=C1N(C)C(N=1)=CC=NC=1NC1=CC=C(C)C(S(N)(=O)=O)=C1 CUIHSIWYWATEQL-UHFFFAOYSA-N 0.000 description 2
- 230000000149 penetrating effect Effects 0.000 description 2
- 229940049954 penicillin Drugs 0.000 description 2
- FPVKHBSQESCIEP-JQCXWYLXSA-N pentostatin Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(N=CNC[C@H]2O)=C2N=C1 FPVKHBSQESCIEP-JQCXWYLXSA-N 0.000 description 2
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 2
- 238000010647 peptide synthesis reaction Methods 0.000 description 2
- 230000008782 phagocytosis Effects 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 102000020233 phosphotransferase Human genes 0.000 description 2
- 230000035790 physiological processes and functions Effects 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- 229960003171 plicamycin Drugs 0.000 description 2
- 229920000771 poly (alkylcyanoacrylate) Polymers 0.000 description 2
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 2
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 2
- 229940068977 polysorbate 20 Drugs 0.000 description 2
- 229920000053 polysorbate 80 Polymers 0.000 description 2
- 229940068968 polysorbate 80 Drugs 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 150000003141 primary amines Chemical class 0.000 description 2
- 150000003147 proline derivatives Chemical class 0.000 description 2
- 229940048914 protamine Drugs 0.000 description 2
- GZUITABIAKMVPG-UHFFFAOYSA-N raloxifene Chemical compound C1=CC(O)=CC=C1C1=C(C(=O)C=2C=CC(OCCN3CCCCC3)=CC=2)C2=CC=C(O)C=C2S1 GZUITABIAKMVPG-UHFFFAOYSA-N 0.000 description 2
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 2
- 229910052703 rhodium Inorganic materials 0.000 description 2
- 239000010948 rhodium Substances 0.000 description 2
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 2
- FCCGJTKEKXUBFZ-UHFFFAOYSA-N rucaparib phosphate Chemical compound OP(O)(O)=O.C1=CC(CNC)=CC=C1C(N1)=C2CCNC(=O)C3=C2C1=CC(F)=C3 FCCGJTKEKXUBFZ-UHFFFAOYSA-N 0.000 description 2
- 229910052707 ruthenium Inorganic materials 0.000 description 2
- KZUNJOHGWZRPMI-UHFFFAOYSA-N samarium atom Chemical compound [Sm] KZUNJOHGWZRPMI-UHFFFAOYSA-N 0.000 description 2
- 239000012723 sample buffer Substances 0.000 description 2
- CYOHGALHFOKKQC-UHFFFAOYSA-N selumetinib Chemical compound OCCONC(=O)C=1C=C2N(C)C=NC2=C(F)C=1NC1=CC=C(Br)C=C1Cl CYOHGALHFOKKQC-UHFFFAOYSA-N 0.000 description 2
- 230000009919 sequestration Effects 0.000 description 2
- 125000003607 serino group Chemical group [H]N([H])[C@]([H])(C(=O)[*])C(O[H])([H])[H] 0.000 description 2
- 238000010008 shearing Methods 0.000 description 2
- 229910052709 silver Inorganic materials 0.000 description 2
- 239000004332 silver Substances 0.000 description 2
- 210000003491 skin Anatomy 0.000 description 2
- 210000000813 small intestine Anatomy 0.000 description 2
- 239000001488 sodium phosphate Substances 0.000 description 2
- 229910000162 sodium phosphate Inorganic materials 0.000 description 2
- 235000011008 sodium phosphates Nutrition 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000007619 statistical method Methods 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 229960005322 streptomycin Drugs 0.000 description 2
- ZSJLQEPLLKMAKR-GKHCUFPYSA-N streptozocin Chemical compound O=NN(C)C(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O ZSJLQEPLLKMAKR-GKHCUFPYSA-N 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 150000005846 sugar alcohols Polymers 0.000 description 2
- 238000013268 sustained release Methods 0.000 description 2
- 239000012730 sustained-release form Substances 0.000 description 2
- 238000012353 t test Methods 0.000 description 2
- NRUKOCRGYNPUPR-QBPJDGROSA-N teniposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@@H](OC[C@H]4O3)C=3SC=CC=3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 NRUKOCRGYNPUPR-QBPJDGROSA-N 0.000 description 2
- 238000011191 terminal modification Methods 0.000 description 2
- 231100001274 therapeutic index Toxicity 0.000 description 2
- 235000008521 threonine Nutrition 0.000 description 2
- 229960004072 thrombin Drugs 0.000 description 2
- 230000000699 topical effect Effects 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- 229960004066 trametinib Drugs 0.000 description 2
- LIRYPHYGHXZJBZ-UHFFFAOYSA-N trametinib Chemical compound CC(=O)NC1=CC=CC(N2C(N(C3CC3)C(=O)C3=C(NC=4C(=CC(I)=CC=4)F)N(C)C(=O)C(C)=C32)=O)=C1 LIRYPHYGHXZJBZ-UHFFFAOYSA-N 0.000 description 2
- 238000003146 transient transfection Methods 0.000 description 2
- 230000032258 transport Effects 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 2
- 241001529453 unidentified herpesvirus Species 0.000 description 2
- LLDWLPRYLVPDTG-UHFFFAOYSA-N vatalanib succinate Chemical compound OC(=O)CCC(O)=O.C1=CC(Cl)=CC=C1NC(C1=CC=CC=C11)=NN=C1CC1=CC=NC=C1 LLDWLPRYLVPDTG-UHFFFAOYSA-N 0.000 description 2
- YTZALCGQUPRCGW-ZSFNYQMMSA-N verteporfin Chemical compound N1C(C=C2C(=C(CCC(O)=O)C(C=C3C(CCC(=O)OC)=C(C)C(N3)=C3)=N2)C)=C(C=C)C(C)=C1C=C1C2=CC=C(C(=O)OC)[C@@H](C(=O)OC)[C@@]2(C)C3=N1 YTZALCGQUPRCGW-ZSFNYQMMSA-N 0.000 description 2
- JXLYSJRDGCGARV-CFWMRBGOSA-N vinblastine Chemical compound C([C@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-CFWMRBGOSA-N 0.000 description 2
- 230000010463 virion release Effects 0.000 description 2
- 230000003612 virological effect Effects 0.000 description 2
- QDLHCMPXEPAAMD-QAIWCSMKSA-N wortmannin Chemical compound C1([C@]2(C)C3=C(C4=O)OC=C3C(=O)O[C@@H]2COC)=C4[C@@H]2CCC(=O)[C@@]2(C)C[C@H]1OC(C)=O QDLHCMPXEPAAMD-QAIWCSMKSA-N 0.000 description 2
- 229940051021 yellow-fever virus Drugs 0.000 description 2
- HBOMLICNUCNMMY-XLPZGREQSA-N zidovudine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](N=[N+]=[N-])C1 HBOMLICNUCNMMY-XLPZGREQSA-N 0.000 description 2
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 description 1
- FBDOJYYTMIHHDH-OZBJMMHXSA-N (19S)-19-ethyl-19-hydroxy-17-oxa-3,13-diazapentacyclo[11.8.0.02,11.04,9.015,20]henicosa-2,4,6,8,10,14,20-heptaen-18-one Chemical compound CC[C@@]1(O)C(=O)OCC2=CN3Cc4cc5ccccc5nc4C3C=C12 FBDOJYYTMIHHDH-OZBJMMHXSA-N 0.000 description 1
- ZJIFDEVVTPEXDL-UHFFFAOYSA-N (2,5-dioxopyrrolidin-1-yl) hydrogen carbonate Chemical compound OC(=O)ON1C(=O)CCC1=O ZJIFDEVVTPEXDL-UHFFFAOYSA-N 0.000 description 1
- HBUBKKRHXORPQB-FJFJXFQQSA-N (2R,3S,4S,5R)-2-(6-amino-2-fluoro-9-purinyl)-5-(hydroxymethyl)oxolane-3,4-diol Chemical compound C1=NC=2C(N)=NC(F)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1O HBUBKKRHXORPQB-FJFJXFQQSA-N 0.000 description 1
- GRZXWCHAXNAUHY-NSISKUIASA-N (2S)-2-(4-chlorophenyl)-1-[4-[(5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]-1-piperazinyl]-3-(propan-2-ylamino)-1-propanone Chemical compound C1([C@H](C(=O)N2CCN(CC2)C=2C=3[C@H](C)C[C@@H](O)C=3N=CN=2)CNC(C)C)=CC=C(Cl)C=C1 GRZXWCHAXNAUHY-NSISKUIASA-N 0.000 description 1
- STUWGJZDJHPWGZ-LBPRGKRZSA-N (2S)-N1-[4-methyl-5-[2-(1,1,1-trifluoro-2-methylpropan-2-yl)-4-pyridinyl]-2-thiazolyl]pyrrolidine-1,2-dicarboxamide Chemical compound S1C(C=2C=C(N=CC=2)C(C)(C)C(F)(F)F)=C(C)N=C1NC(=O)N1CCC[C@H]1C(N)=O STUWGJZDJHPWGZ-LBPRGKRZSA-N 0.000 description 1
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 description 1
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- QVVDVENEPNODSI-BTNSXGMBSA-N (2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-amino-5-(diaminomethylideneamino)pentanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]-5-(diaminomethylidene Chemical compound NC(N)=NCCC[C@H](N)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O QVVDVENEPNODSI-BTNSXGMBSA-N 0.000 description 1
- SVNJBEMPMKWDCO-KCHLEUMXSA-N (2s)-2-[[(2s)-3-carboxy-2-[[2-[[(2s)-5-(diaminomethylideneamino)-2-[[4-oxo-4-[[4-(4-oxo-8-phenylchromen-2-yl)morpholin-4-ium-4-yl]methoxy]butanoyl]amino]pentanoyl]amino]acetyl]amino]propanoyl]amino]-3-hydroxypropanoate Chemical compound C=1C(=O)C2=CC=CC(C=3C=CC=CC=3)=C2OC=1[N+]1(COC(=O)CCC(=O)N[C@@H](CCCNC(=N)N)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C([O-])=O)CCOCC1 SVNJBEMPMKWDCO-KCHLEUMXSA-N 0.000 description 1
- WGOIHPRRFBCVBZ-VKHMYHEASA-N (2s)-5-oxopyrrolidine-2-carboxamide Chemical compound NC(=O)[C@@H]1CCC(=O)N1 WGOIHPRRFBCVBZ-VKHMYHEASA-N 0.000 description 1
- DMQYDVBIPXAAJA-VHXPQNKSSA-N (3z)-5-[(1-ethylpiperidin-4-yl)amino]-3-[(3-fluorophenyl)-(5-methyl-1h-imidazol-2-yl)methylidene]-1h-indol-2-one Chemical compound C1CN(CC)CCC1NC1=CC=C(NC(=O)\C2=C(/C=3NC=C(C)N=3)C=3C=C(F)C=CC=3)C2=C1 DMQYDVBIPXAAJA-VHXPQNKSSA-N 0.000 description 1
- MWWSFMDVAYGXBV-MYPASOLCSA-N (7r,9s)-7-[(2r,4s,5s,6s)-4-amino-5-hydroxy-6-methyloxan-2-yl]oxy-6,9,11-trihydroxy-9-(2-hydroxyacetyl)-4-methoxy-8,10-dihydro-7h-tetracene-5,12-dione;hydrochloride Chemical compound Cl.O([C@@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 MWWSFMDVAYGXBV-MYPASOLCSA-N 0.000 description 1
- BDPXTYNYUJHKCI-UFQCMFJCSA-N (8R,9S,10R,13S,14R,17S)-15-(fluoromethyl)-17-hydroxy-10,13-dimethyl-1,2,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-3-one Chemical compound FCC1[C@@H]2[C@]([C@H](C1)O)(C)CC[C@H]1[C@H]2CCC2=CC(=O)CC[C@]12C BDPXTYNYUJHKCI-UFQCMFJCSA-N 0.000 description 1
- FPVKHBSQESCIEP-UHFFFAOYSA-N (8S)-3-(2-deoxy-beta-D-erythro-pentofuranosyl)-3,6,7,8-tetrahydroimidazo[4,5-d][1,3]diazepin-8-ol Natural products C1C(O)C(CO)OC1N1C(NC=NCC2O)=C2N=C1 FPVKHBSQESCIEP-UHFFFAOYSA-N 0.000 description 1
- FDKXTQMXEQVLRF-ZHACJKMWSA-N (E)-dacarbazine Chemical compound CN(C)\N=N\c1[nH]cnc1C(N)=O FDKXTQMXEQVLRF-ZHACJKMWSA-N 0.000 description 1
- RTHCYVBBDHJXIQ-MRXNPFEDSA-N (R)-fluoxetine Chemical compound O([C@H](CCNC)C=1C=CC=CC=1)C1=CC=C(C(F)(F)F)C=C1 RTHCYVBBDHJXIQ-MRXNPFEDSA-N 0.000 description 1
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 1
- UKAUYVFTDYCKQA-UHFFFAOYSA-N -2-Amino-4-hydroxybutanoic acid Natural products OC(=O)C(N)CCO UKAUYVFTDYCKQA-UHFFFAOYSA-N 0.000 description 1
- MHCVCKDNQYMGEX-UHFFFAOYSA-N 1,1'-biphenyl;phenoxybenzene Chemical compound C1=CC=CC=C1C1=CC=CC=C1.C=1C=CC=CC=1OC1=CC=CC=C1 MHCVCKDNQYMGEX-UHFFFAOYSA-N 0.000 description 1
- WNXJIVFYUVYPPR-UHFFFAOYSA-N 1,3-dioxolane Chemical compound C1COCO1 WNXJIVFYUVYPPR-UHFFFAOYSA-N 0.000 description 1
- HJTAZXHBEBIQQX-UHFFFAOYSA-N 1,5-bis(chloromethyl)naphthalene Chemical compound C1=CC=C2C(CCl)=CC=CC2=C1CCl HJTAZXHBEBIQQX-UHFFFAOYSA-N 0.000 description 1
- WOXWUZCRWJWTRT-UHFFFAOYSA-N 1-amino-1-cyclohexanecarboxylic acid Chemical group OC(=O)C1(N)CCCCC1 WOXWUZCRWJWTRT-UHFFFAOYSA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- CTLOSZHDGZLOQE-UHFFFAOYSA-N 14-methoxy-9-[(4-methylpiperazin-1-yl)methyl]-9,19-diazapentacyclo[10.7.0.02,6.07,11.013,18]nonadeca-1(12),2(6),7(11),13(18),14,16-hexaene-8,10-dione Chemical compound O=C1C2=C3C=4C(OC)=CC=CC=4NC3=C3CCCC3=C2C(=O)N1CN1CCN(C)CC1 CTLOSZHDGZLOQE-UHFFFAOYSA-N 0.000 description 1
- VFYFMNCKPJDAPV-UHFFFAOYSA-N 2,2'-(5-oxo-1,3-dioxolan-4,4-diyl)diessigs Chemical compound C1N(C2)CN3CN1CN2C3.OC(=O)CC1(CC(O)=O)OCOC1=O VFYFMNCKPJDAPV-UHFFFAOYSA-N 0.000 description 1
- VPMMJSPGZSFEAH-UHFFFAOYSA-N 2,4-diaminophenol;hydrochloride Chemical compound [Cl-].NC1=CC=C(O)C([NH3+])=C1 VPMMJSPGZSFEAH-UHFFFAOYSA-N 0.000 description 1
- OMGHIGVFLOPEHJ-UHFFFAOYSA-N 2,5-dihydro-1h-pyrrol-1-ium-2-carboxylate Chemical compound OC(=O)C1NCC=C1 OMGHIGVFLOPEHJ-UHFFFAOYSA-N 0.000 description 1
- ASJSXUWOFZATJM-UHFFFAOYSA-N 2-(3,5-diphenyl-1h-tetrazol-2-yl)-4,5-dimethyl-1,3-thiazole Chemical compound S1C(C)=C(C)N=C1N1N(C=2C=CC=CC=2)NC(C=2C=CC=CC=2)=N1 ASJSXUWOFZATJM-UHFFFAOYSA-N 0.000 description 1
- OGAULEBSQQMUKP-UHFFFAOYSA-N 2-(4-aminobutylamino)acetic acid Chemical compound NCCCCNCC(O)=O OGAULEBSQQMUKP-UHFFFAOYSA-N 0.000 description 1
- VZTMYLWJKCAXMZ-UHFFFAOYSA-N 2-[(2-chloroquinazolin-4-yl)amino]ethanol Chemical compound C1=CC=C2C(NCCO)=NC(Cl)=NC2=C1 VZTMYLWJKCAXMZ-UHFFFAOYSA-N 0.000 description 1
- DSBSVDCHFMEYBX-FFXKMJQXSA-N 2-[(2r)-2-methylpyrrolidin-2-yl]-1h-benzimidazole-4-carboxamide;dihydrochloride Chemical compound Cl.Cl.N=1C2=C(C(N)=O)C=CC=C2NC=1[C@@]1(C)CCCN1 DSBSVDCHFMEYBX-FFXKMJQXSA-N 0.000 description 1
- MWYDSXOGIBMAET-UHFFFAOYSA-N 2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydro-1H-imidazo[1,2-c]quinazolin-5-ylidene]pyrimidine-5-carboxamide Chemical compound NC1=NC=C(C=N1)C(=O)N=C1N=C2C(=C(C=CC2=C2N1CCN2)OCCCN1CCOCC1)OC MWYDSXOGIBMAET-UHFFFAOYSA-N 0.000 description 1
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 description 1
- CDAWCLOXVUBKRW-UHFFFAOYSA-N 2-aminophenol Chemical compound NC1=CC=CC=C1O CDAWCLOXVUBKRW-UHFFFAOYSA-N 0.000 description 1
- CBIAKDAYHRWZCU-UHFFFAOYSA-N 2-bromo-4-[(6,7-dimethoxyquinazolin-4-yl)amino]phenol Chemical compound C=12C=C(OC)C(OC)=CC2=NC=NC=1NC1=CC=C(O)C(Br)=C1 CBIAKDAYHRWZCU-UHFFFAOYSA-N 0.000 description 1
- ZZUZYEMRHCMVTB-UHFFFAOYSA-N 2-phenylethynesulfonamide Chemical compound NS(=O)(=O)C#CC1=CC=CC=C1 ZZUZYEMRHCMVTB-UHFFFAOYSA-N 0.000 description 1
- ZSLUVFAKFWKJRC-IGMARMGPSA-N 232Th Chemical compound [232Th] ZSLUVFAKFWKJRC-IGMARMGPSA-N 0.000 description 1
- BTBWSRPRAGXJJV-UHFFFAOYSA-N 2h-benzotriazole;carbonic acid Chemical compound OC(O)=O.C1=CC=C2NN=NC2=C1 BTBWSRPRAGXJJV-UHFFFAOYSA-N 0.000 description 1
- AZKSAVLVSZKNRD-UHFFFAOYSA-M 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide Chemical compound [Br-].S1C(C)=C(C)N=C1[N+]1=NC(C=2C=CC=CC=2)=NN1C1=CC=CC=C1 AZKSAVLVSZKNRD-UHFFFAOYSA-M 0.000 description 1
- WGYPOAXANMFHMT-UHFFFAOYSA-N 3-(4-amino-1-propan-2-ylpyrazolo[3,4-d]pyrimidin-3-yl)-n-(4,5-dihydro-1,3-thiazol-2-yl)benzamide Chemical compound C12=C(N)N=CN=C2N(C(C)C)N=C1C(C=1)=CC=CC=1C(=O)NC1=NCCS1 WGYPOAXANMFHMT-UHFFFAOYSA-N 0.000 description 1
- RCLQNICOARASSR-SECBINFHSA-N 3-[(2r)-2,3-dihydroxypropyl]-6-fluoro-5-(2-fluoro-4-iodoanilino)-8-methylpyrido[2,3-d]pyrimidine-4,7-dione Chemical compound FC=1C(=O)N(C)C=2N=CN(C[C@@H](O)CO)C(=O)C=2C=1NC1=CC=C(I)C=C1F RCLQNICOARASSR-SECBINFHSA-N 0.000 description 1
- WUIABRMSWOKTOF-OYALTWQYSA-N 3-[[2-[2-[2-[[(2s,3r)-2-[[(2s,3s,4r)-4-[[(2s,3r)-2-[[6-amino-2-[(1s)-3-amino-1-[[(2s)-2,3-diamino-3-oxopropyl]amino]-3-oxopropyl]-5-methylpyrimidine-4-carbonyl]amino]-3-[(2r,3s,4s,5s,6s)-3-[(2r,3s,4s,5r,6r)-4-carbamoyloxy-3,5-dihydroxy-6-(hydroxymethyl)ox Chemical compound OS([O-])(=O)=O.N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1NC=NC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C WUIABRMSWOKTOF-OYALTWQYSA-N 0.000 description 1
- 125000006279 3-bromobenzyl group Chemical group [H]C1=C([H])C(=C([H])C(Br)=C1[H])C([H])([H])* 0.000 description 1
- IHDBZCJYSHDCKF-UHFFFAOYSA-N 4,6-dichlorotriazine Chemical class ClC1=CC(Cl)=NN=N1 IHDBZCJYSHDCKF-UHFFFAOYSA-N 0.000 description 1
- HOZUXBLMYUPGPZ-UHFFFAOYSA-N 4-[(6,7-dimethoxyquinazolin-4-yl)amino]phenol Chemical compound C=12C=C(OC)C(OC)=CC2=NC=NC=1NC1=CC=C(O)C=C1 HOZUXBLMYUPGPZ-UHFFFAOYSA-N 0.000 description 1
- SYYMNUFXRFAELA-BTQNPOSSSA-N 4-[4-[[(1r)-1-phenylethyl]amino]-7h-pyrrolo[2,3-d]pyrimidin-6-yl]phenol;hydrobromide Chemical compound Br.N([C@H](C)C=1C=CC=CC=1)C(C=1C=2)=NC=NC=1NC=2C1=CC=C(O)C=C1 SYYMNUFXRFAELA-BTQNPOSSSA-N 0.000 description 1
- FPEIJQLXFHKLJV-UHFFFAOYSA-N 4-[6-(1h-indol-5-yl)-1-[1-(pyridin-3-ylmethyl)piperidin-4-yl]pyrazolo[3,4-d]pyrimidin-4-yl]morpholine Chemical compound C=1C=CN=CC=1CN(CC1)CCC1N(C1=NC(=N2)C=3C=C4C=CNC4=CC=3)N=CC1=C2N1CCOCC1 FPEIJQLXFHKLJV-UHFFFAOYSA-N 0.000 description 1
- IMXHGCRIEAKIBU-UHFFFAOYSA-N 4-[6-[4-(methoxycarbonylamino)phenyl]-4-(4-morpholinyl)-1-pyrazolo[3,4-d]pyrimidinyl]-1-piperidinecarboxylic acid methyl ester Chemical compound C1=CC(NC(=O)OC)=CC=C1C1=NC(N2CCOCC2)=C(C=NN2C3CCN(CC3)C(=O)OC)C2=N1 IMXHGCRIEAKIBU-UHFFFAOYSA-N 0.000 description 1
- FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 description 1
- UHDGCWIWMRVCDJ-STUHELBRSA-N 4-amino-1-[(3s,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]pyrimidin-2-one Chemical compound O=C1N=C(N)C=CN1C1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-STUHELBRSA-N 0.000 description 1
- HSBKFSPNDWWPSL-VDTYLAMSSA-N 4-amino-5-fluoro-1-[(2s,5r)-5-(hydroxymethyl)-2,5-dihydrofuran-2-yl]pyrimidin-2-one Chemical compound C1=C(F)C(N)=NC(=O)N1[C@@H]1C=C[C@H](CO)O1 HSBKFSPNDWWPSL-VDTYLAMSSA-N 0.000 description 1
- JDUBGYFRJFOXQC-KRWDZBQOSA-N 4-amino-n-[(1s)-1-(4-chlorophenyl)-3-hydroxypropyl]-1-(7h-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide Chemical compound C1([C@H](CCO)NC(=O)C2(CCN(CC2)C=2C=3C=CNC=3N=CN=2)N)=CC=C(Cl)C=C1 JDUBGYFRJFOXQC-KRWDZBQOSA-N 0.000 description 1
- 125000004042 4-aminobutyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])N([H])[H] 0.000 description 1
- GYLDXIAOMVERTK-UHFFFAOYSA-N 5-(4-amino-1-propan-2-yl-3-pyrazolo[3,4-d]pyrimidinyl)-1,3-benzoxazol-2-amine Chemical compound C12=C(N)N=CN=C2N(C(C)C)N=C1C1=CC=C(OC(N)=N2)C2=C1 GYLDXIAOMVERTK-UHFFFAOYSA-N 0.000 description 1
- NMUSYJAQQFHJEW-KVTDHHQDSA-N 5-azacytidine Chemical compound O=C1N=C(N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 NMUSYJAQQFHJEW-KVTDHHQDSA-N 0.000 description 1
- RBBWQDOANHSGRX-UHFFFAOYSA-N 5-nitro-n-(thiophen-2-ylmethyl)furan-2-carboxamide Chemical compound O1C([N+](=O)[O-])=CC=C1C(=O)NCC1=CC=CS1 RBBWQDOANHSGRX-UHFFFAOYSA-N 0.000 description 1
- LFYOZCBFOSSLNJ-UHFFFAOYSA-N 8-[4-(1-aminocyclobutyl)phenyl]-9-phenyl-2h-[1,2,4]triazolo[3,4-f][1,6]naphthyridin-3-one;hydrochloride Chemical compound Cl.C=1C=C(C=2C(=CC=3C4=NN=C(O)N4C=CC=3N=2)C=2C=CC=CC=2)C=CC=1C1(N)CCC1 LFYOZCBFOSSLNJ-UHFFFAOYSA-N 0.000 description 1
- SJVQHLPISAIATJ-ZDUSSCGKSA-N 8-chloro-2-phenyl-3-[(1S)-1-(7H-purin-6-ylamino)ethyl]-1-isoquinolinone Chemical compound C1([C@@H](NC=2C=3N=CNC=3N=CN=2)C)=CC2=CC=CC(Cl)=C2C(=O)N1C1=CC=CC=C1 SJVQHLPISAIATJ-ZDUSSCGKSA-N 0.000 description 1
- KVLFRAWTRWDEDF-IRXDYDNUSA-N AZD-8055 Chemical compound C1=C(CO)C(OC)=CC=C1C1=CC=C(C(=NC(=N2)N3[C@H](COCC3)C)N3[C@H](COCC3)C)C2=N1 KVLFRAWTRWDEDF-IRXDYDNUSA-N 0.000 description 1
- 239000005660 Abamectin Substances 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 1
- 208000002874 Acne Vulgaris Diseases 0.000 description 1
- 102100022900 Actin, cytoplasmic 1 Human genes 0.000 description 1
- 108010085238 Actins Proteins 0.000 description 1
- 208000016557 Acute basophilic leukemia Diseases 0.000 description 1
- 206010000871 Acute monocytic leukaemia Diseases 0.000 description 1
- 241000321096 Adenoides Species 0.000 description 1
- 208000003200 Adenoma Diseases 0.000 description 1
- 206010001233 Adenoma benign Diseases 0.000 description 1
- 208000006468 Adrenal Cortex Neoplasms Diseases 0.000 description 1
- 208000009746 Adult T-Cell Leukemia-Lymphoma Diseases 0.000 description 1
- 208000016683 Adult T-cell leukemia/lymphoma Diseases 0.000 description 1
- ULXXDDBFHOBEHA-ONEGZZNKSA-N Afatinib Chemical compound N1=CN=C2C=C(OC3COCC3)C(NC(=O)/C=C/CN(C)C)=CC2=C1NC1=CC=C(F)C(Cl)=C1 ULXXDDBFHOBEHA-ONEGZZNKSA-N 0.000 description 1
- NJWJSLCQEDMGNC-MBLNEYKQSA-N Ala-His-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC1=CN=CN1)NC(=O)[C@H](C)N)O NJWJSLCQEDMGNC-MBLNEYKQSA-N 0.000 description 1
- UWIQWPWWZUHBAO-ZLIFDBKOSA-N Ala-Leu-Trp Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@@H](NC(=O)[C@H](C)N)CC(C)C)C(O)=O)=CNC2=C1 UWIQWPWWZUHBAO-ZLIFDBKOSA-N 0.000 description 1
- XHNLCGXYBXNRIS-BJDJZHNGSA-N Ala-Lys-Ile Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O XHNLCGXYBXNRIS-BJDJZHNGSA-N 0.000 description 1
- KLALXKYLOMZDQT-ZLUOBGJFSA-N Ala-Ser-Asn Chemical compound C[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CC(N)=O KLALXKYLOMZDQT-ZLUOBGJFSA-N 0.000 description 1
- MUGAESARFRGOTQ-IGNZVWTISA-N Ala-Tyr-Tyr Chemical compound C[C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)N[C@@H](CC2=CC=C(C=C2)O)C(=O)O)N MUGAESARFRGOTQ-IGNZVWTISA-N 0.000 description 1
- XCIGOVDXZULBBV-DCAQKATOSA-N Ala-Val-Lys Chemical compound CC(C)[C@H](NC(=O)[C@H](C)N)C(=O)N[C@@H](CCCCN)C(O)=O XCIGOVDXZULBBV-DCAQKATOSA-N 0.000 description 1
- 108010012934 Albumin-Bound Paclitaxel Proteins 0.000 description 1
- 241000710929 Alphavirus Species 0.000 description 1
- 208000037540 Alveolar soft tissue sarcoma Diseases 0.000 description 1
- 201000003076 Angiosarcoma Diseases 0.000 description 1
- 108091023037 Aptamer Proteins 0.000 description 1
- 101100165655 Arabidopsis thaliana BRO1 gene Proteins 0.000 description 1
- 241000712892 Arenaviridae Species 0.000 description 1
- BHSYMWWMVRPCPA-CYDGBPFRSA-N Arg-Arg-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@@H](N)CCCN=C(N)N BHSYMWWMVRPCPA-CYDGBPFRSA-N 0.000 description 1
- UISQLSIBJKEJSS-GUBZILKMSA-N Arg-Arg-Ser Chemical compound NC(N)=NCCC[C@H](N)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CO)C(O)=O UISQLSIBJKEJSS-GUBZILKMSA-N 0.000 description 1
- KWTVWJPNHAOREN-IHRRRGAJSA-N Arg-Asn-Phe Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O KWTVWJPNHAOREN-IHRRRGAJSA-N 0.000 description 1
- JCAISGGAOQXEHJ-ZPFDUUQYSA-N Arg-Gln-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CCCN=C(N)N)N JCAISGGAOQXEHJ-ZPFDUUQYSA-N 0.000 description 1
- WVNFNPGXYADPPO-BQBZGAKWSA-N Arg-Gly-Ser Chemical compound NC(N)=NCCC[C@H](N)C(=O)NCC(=O)N[C@@H](CO)C(O)=O WVNFNPGXYADPPO-BQBZGAKWSA-N 0.000 description 1
- NMRHDSAOIURTNT-RWMBFGLXSA-N Arg-Leu-Pro Chemical compound CC(C)C[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CCCN=C(N)N)N NMRHDSAOIURTNT-RWMBFGLXSA-N 0.000 description 1
- NYDIVDKTULRINZ-AVGNSLFASA-N Arg-Met-Lys Chemical compound CSCC[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CCCN=C(N)N)N NYDIVDKTULRINZ-AVGNSLFASA-N 0.000 description 1
- HGKHPCFTRQDHCU-IUCAKERBSA-N Arg-Pro-Gly Chemical compound NC(N)=NCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)NCC(O)=O HGKHPCFTRQDHCU-IUCAKERBSA-N 0.000 description 1
- NGYHSXDNNOFHNE-AVGNSLFASA-N Arg-Pro-Leu Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(C)C)C(O)=O NGYHSXDNNOFHNE-AVGNSLFASA-N 0.000 description 1
- YCYXHLZRUSJITQ-SRVKXCTJSA-N Arg-Pro-Pro Chemical compound NC(=N)NCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(O)=O)CCC1 YCYXHLZRUSJITQ-SRVKXCTJSA-N 0.000 description 1
- SYFHFLGAROUHNT-VEVYYDQMSA-N Arg-Thr-Asn Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(O)=O SYFHFLGAROUHNT-VEVYYDQMSA-N 0.000 description 1
- WTFIFQWLQXZLIZ-UMPQAUOISA-N Arg-Thr-Trp Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)O)NC(=O)[C@H](CCCN=C(N)N)N)O WTFIFQWLQXZLIZ-UMPQAUOISA-N 0.000 description 1
- VLIJAPRTSXSGFY-STQMWFEESA-N Arg-Tyr-Gly Chemical compound NC(N)=NCCC[C@H](N)C(=O)N[C@H](C(=O)NCC(O)=O)CC1=CC=C(O)C=C1 VLIJAPRTSXSGFY-STQMWFEESA-N 0.000 description 1
- HZYFHQOWCFUSOV-IMJSIDKUSA-N Asn-Asp Chemical compound NC(=O)C[C@H](N)C(=O)N[C@@H](CC(O)=O)C(O)=O HZYFHQOWCFUSOV-IMJSIDKUSA-N 0.000 description 1
- MSBDSTRUMZFSEU-PEFMBERDSA-N Asn-Glu-Ile Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O MSBDSTRUMZFSEU-PEFMBERDSA-N 0.000 description 1
- RVHGJNGNKGDCPX-KKUMJFAQSA-N Asn-Phe-Lys Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CC(=O)N)N RVHGJNGNKGDCPX-KKUMJFAQSA-N 0.000 description 1
- OOXUBGLNDRGOKT-FXQIFTODSA-N Asn-Ser-Arg Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O OOXUBGLNDRGOKT-FXQIFTODSA-N 0.000 description 1
- KZYSHAMXEBPJBD-JRQIVUDYSA-N Asn-Thr-Tyr Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O KZYSHAMXEBPJBD-JRQIVUDYSA-N 0.000 description 1
- GBSUGIXJAAKZOW-GMOBBJLQSA-N Asp-Ile-Arg Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O GBSUGIXJAAKZOW-GMOBBJLQSA-N 0.000 description 1
- ZKAOJVJQGVUIIU-GUBZILKMSA-N Asp-Pro-Arg Chemical compound OC(=O)C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCNC(N)=N)C(O)=O ZKAOJVJQGVUIIU-GUBZILKMSA-N 0.000 description 1
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 description 1
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 206010006417 Bronchial carcinoma Diseases 0.000 description 1
- 208000003170 Bronchiolo-Alveolar Adenocarcinoma Diseases 0.000 description 1
- 206010058354 Bronchioloalveolar carcinoma Diseases 0.000 description 1
- 239000002126 C01EB10 - Adenosine Substances 0.000 description 1
- 239000004072 C09CA03 - Valsartan Substances 0.000 description 1
- UFKLYTOEMRFKAD-SHTZXODSSA-N C1C[C@@H](OC)CC[C@@H]1N1C2=NC(C=3C=NC(=CC=3)C(C)(C)O)=CN=C2NCC1=O Chemical compound C1C[C@@H](OC)CC[C@@H]1N1C2=NC(C=3C=NC(=CC=3)C(C)(C)O)=CN=C2NCC1=O UFKLYTOEMRFKAD-SHTZXODSSA-N 0.000 description 1
- QAGYKUNXZHXKMR-UHFFFAOYSA-N CPD000469186 Natural products CC1=C(O)C=CC=C1C(=O)NC(C(O)CN1C(CC2CCCCC2C1)C(=O)NC(C)(C)C)CSC1=CC=CC=C1 QAGYKUNXZHXKMR-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- KLWPJMFMVPTNCC-UHFFFAOYSA-N Camptothecin Natural products CCC1(O)C(=O)OCC2=C1C=C3C4Nc5ccccc5C=C4CN3C2=O KLWPJMFMVPTNCC-UHFFFAOYSA-N 0.000 description 1
- GAGWJHPBXLXJQN-UORFTKCHSA-N Capecitabine Chemical compound C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1[C@H]1[C@H](O)[C@H](O)[C@@H](C)O1 GAGWJHPBXLXJQN-UORFTKCHSA-N 0.000 description 1
- 108090000565 Capsid Proteins Proteins 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 208000009458 Carcinoma in Situ Diseases 0.000 description 1
- 108010078791 Carrier Proteins Proteins 0.000 description 1
- 229920000623 Cellulose acetate phthalate Polymers 0.000 description 1
- 102100023321 Ceruloplasmin Human genes 0.000 description 1
- 206010008342 Cervix carcinoma Diseases 0.000 description 1
- 229920001661 Chitosan Polymers 0.000 description 1
- JWBOIMRXGHLCPP-UHFFFAOYSA-N Chloditan Chemical compound C=1C=CC=C(Cl)C=1C(C(Cl)Cl)C1=CC=C(Cl)C=C1 JWBOIMRXGHLCPP-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 206010008583 Chloroma Diseases 0.000 description 1
- 201000005262 Chondroma Diseases 0.000 description 1
- 208000005243 Chondrosarcoma Diseases 0.000 description 1
- VYZAMTAEIAYCRO-UHFFFAOYSA-N Chromium Chemical compound [Cr] VYZAMTAEIAYCRO-UHFFFAOYSA-N 0.000 description 1
- VWFCHDSQECPREK-LURJTMIESA-N Cidofovir Chemical compound NC=1C=CN(C[C@@H](CO)OCP(O)(O)=O)C(=O)N=1 VWFCHDSQECPREK-LURJTMIESA-N 0.000 description 1
- 241000202285 Claravis Species 0.000 description 1
- 241000252203 Clupea harengus Species 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 108010069112 Complement System Proteins Proteins 0.000 description 1
- 102000000989 Complement System Proteins Human genes 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 101000899237 Corylus avellana Endoplasmic reticulum chaperone BiP Proteins 0.000 description 1
- RWAZRMXTVSIVJR-YUMQZZPRSA-N Cys-Gly-His Chemical compound [H]N[C@@H](CS)C(=O)NCC(=O)N[C@@H](CC1=CNC=N1)C(O)=O RWAZRMXTVSIVJR-YUMQZZPRSA-N 0.000 description 1
- 102000005927 Cysteine Proteases Human genes 0.000 description 1
- 108010005843 Cysteine Proteases Proteins 0.000 description 1
- 108010001202 Cytochrome P-450 CYP2E1 Proteins 0.000 description 1
- 102100039282 Cytochrome P450 26A1 Human genes 0.000 description 1
- 102100024889 Cytochrome P450 2E1 Human genes 0.000 description 1
- 108050008072 Cytochrome c oxidase subunit IV Proteins 0.000 description 1
- 108090000365 Cytochrome-c oxidases Proteins 0.000 description 1
- 108010052832 Cytochromes Proteins 0.000 description 1
- 102000018832 Cytochromes Human genes 0.000 description 1
- ONIBWKKTOPOVIA-SCSAIBSYSA-N D-Proline Chemical compound OC(=O)[C@H]1CCCN1 ONIBWKKTOPOVIA-SCSAIBSYSA-N 0.000 description 1
- 102000053602 DNA Human genes 0.000 description 1
- 230000004568 DNA-binding Effects 0.000 description 1
- 101710088194 Dehydrogenase Proteins 0.000 description 1
- 241000702421 Dependoparvovirus Species 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- BXZVVICBKDXVGW-NKWVEPMBSA-N Didanosine Chemical compound O1[C@H](CO)CC[C@@H]1N1C(NC=NC2=O)=C2N=C1 BXZVVICBKDXVGW-NKWVEPMBSA-N 0.000 description 1
- IIUZTXTZRGLYTI-UHFFFAOYSA-N Dihydrogriseofulvin Natural products COC1CC(=O)CC(C)C11C(=O)C(C(OC)=CC(OC)=C2Cl)=C2O1 IIUZTXTZRGLYTI-UHFFFAOYSA-N 0.000 description 1
- 208000006402 Ductal Carcinoma Diseases 0.000 description 1
- 229910052692 Dysprosium Inorganic materials 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- XPOQHMRABVBWPR-UHFFFAOYSA-N Efavirenz Natural products O1C(=O)NC2=CC=C(Cl)C=C2C1(C(F)(F)F)C#CC1CC1 XPOQHMRABVBWPR-UHFFFAOYSA-N 0.000 description 1
- XQSPYNMVSIKCOC-NTSWFWBYSA-N Emtricitabine Chemical compound C1=C(F)C(N)=NC(=O)N1[C@H]1O[C@@H](CO)SC1 XQSPYNMVSIKCOC-NTSWFWBYSA-N 0.000 description 1
- 206010014733 Endometrial cancer Diseases 0.000 description 1
- 206010014759 Endometrial neoplasm Diseases 0.000 description 1
- 206010057649 Endometrial sarcoma Diseases 0.000 description 1
- 241000991587 Enterovirus C Species 0.000 description 1
- 101710091045 Envelope protein Proteins 0.000 description 1
- 206010014958 Eosinophilic leukaemia Diseases 0.000 description 1
- 229910052691 Erbium Inorganic materials 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- 208000000461 Esophageal Neoplasms Diseases 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 1
- 229910052693 Europium Inorganic materials 0.000 description 1
- 208000006168 Ewing Sarcoma Diseases 0.000 description 1
- 102000015212 Fas Ligand Protein Human genes 0.000 description 1
- 108010039471 Fas Ligand Protein Proteins 0.000 description 1
- 108010087819 Fc receptors Proteins 0.000 description 1
- 102000009109 Fc receptors Human genes 0.000 description 1
- 108010088842 Fibrinolysin Proteins 0.000 description 1
- 102100028072 Fibroblast growth factor 4 Human genes 0.000 description 1
- 201000008808 Fibrosarcoma Diseases 0.000 description 1
- 241000710781 Flaviviridae Species 0.000 description 1
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 1
- VWUXBMIQPBEWFH-WCCTWKNTSA-N Fulvestrant Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3[C@H](CCCCCCCCCS(=O)CCCC(F)(F)C(F)(F)F)CC2=C1 VWUXBMIQPBEWFH-WCCTWKNTSA-N 0.000 description 1
- 230000037059 G2/M phase arrest Effects 0.000 description 1
- 108010092526 GKPV peptide Proteins 0.000 description 1
- 229910052688 Gadolinium Inorganic materials 0.000 description 1
- GYHNNYVSQQEPJS-UHFFFAOYSA-N Gallium Chemical compound [Ga] GYHNNYVSQQEPJS-UHFFFAOYSA-N 0.000 description 1
- 208000021309 Germ cell tumor Diseases 0.000 description 1
- 102000006395 Globulins Human genes 0.000 description 1
- 108010044091 Globulins Proteins 0.000 description 1
- FHPXTPQBODWBIY-CIUDSAMLSA-N Glu-Ala-Arg Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O FHPXTPQBODWBIY-CIUDSAMLSA-N 0.000 description 1
- LXAUHIRMWXQRKI-XHNCKOQMSA-N Glu-Asn-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC(=O)N)NC(=O)[C@H](CCC(=O)O)N)C(=O)O LXAUHIRMWXQRKI-XHNCKOQMSA-N 0.000 description 1
- BUAKRRKDHSSIKK-IHRRRGAJSA-N Glu-Glu-Tyr Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 BUAKRRKDHSSIKK-IHRRRGAJSA-N 0.000 description 1
- HMJULNMJWOZNFI-XHNCKOQMSA-N Glu-Ser-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CO)NC(=O)[C@H](CCC(=O)O)N)C(=O)O HMJULNMJWOZNFI-XHNCKOQMSA-N 0.000 description 1
- VIPDPMHGICREIS-GVXVVHGQSA-N Glu-Val-Leu Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O VIPDPMHGICREIS-GVXVVHGQSA-N 0.000 description 1
- LHYJCVCQPWRMKZ-WEDXCCLWSA-N Gly-Leu-Thr Chemical compound [H]NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O LHYJCVCQPWRMKZ-WEDXCCLWSA-N 0.000 description 1
- CLNSYANKYVMZNM-UWVGGRQHSA-N Gly-Lys-Arg Chemical compound NCCCC[C@H](NC(=O)CN)C(=O)N[C@H](C(O)=O)CCCN=C(N)N CLNSYANKYVMZNM-UWVGGRQHSA-N 0.000 description 1
- JYPCXBJRLBHWME-IUCAKERBSA-N Gly-Pro-Arg Chemical compound NCC(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCNC(N)=N)C(O)=O JYPCXBJRLBHWME-IUCAKERBSA-N 0.000 description 1
- IRJWAYCXIYUHQE-WHFBIAKZSA-N Gly-Ser-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)CN IRJWAYCXIYUHQE-WHFBIAKZSA-N 0.000 description 1
- YXTFLTJYLIAZQG-FJXKBIBVSA-N Gly-Thr-Arg Chemical compound NCC(=O)N[C@@H]([C@H](O)C)C(=O)N[C@H](C(O)=O)CCCN=C(N)N YXTFLTJYLIAZQG-FJXKBIBVSA-N 0.000 description 1
- HQSKKSLNLSTONK-JTQLQIEISA-N Gly-Tyr-Gly Chemical compound OC(=O)CNC(=O)[C@@H](NC(=O)CN)CC1=CC=C(O)C=C1 HQSKKSLNLSTONK-JTQLQIEISA-N 0.000 description 1
- JZNWSCPGTDBMEW-UHFFFAOYSA-N Glycerophosphorylethanolamin Natural products NCCOP(O)(=O)OCC(O)CO JZNWSCPGTDBMEW-UHFFFAOYSA-N 0.000 description 1
- 102000003886 Glycoproteins Human genes 0.000 description 1
- 108090000288 Glycoproteins Proteins 0.000 description 1
- UXWOXTQWVMFRSE-UHFFFAOYSA-N Griseoviridin Natural products O=C1OC(C)CC=C(C(NCC=CC=CC(O)CC(O)C2)=O)SCC1NC(=O)C1=COC2=N1 UXWOXTQWVMFRSE-UHFFFAOYSA-N 0.000 description 1
- RVKIPWVMZANZLI-UHFFFAOYSA-N H-Lys-Trp-OH Natural products C1=CC=C2C(CC(NC(=O)C(N)CCCCN)C(O)=O)=CNC2=C1 RVKIPWVMZANZLI-UHFFFAOYSA-N 0.000 description 1
- 208000037357 HIV infectious disease Diseases 0.000 description 1
- 208000001258 Hemangiosarcoma Diseases 0.000 description 1
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 1
- 241000700721 Hepatitis B virus Species 0.000 description 1
- XINDHUAGVGCNSF-QSFUFRPTSA-N His-Ala-Ile Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](C)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O XINDHUAGVGCNSF-QSFUFRPTSA-N 0.000 description 1
- NOQPTNXSGNPJNS-YUMQZZPRSA-N His-Asn-Gly Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(O)=O NOQPTNXSGNPJNS-YUMQZZPRSA-N 0.000 description 1
- JENKOCSDMSVWPY-SRVKXCTJSA-N His-Leu-Asn Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(O)=O JENKOCSDMSVWPY-SRVKXCTJSA-N 0.000 description 1
- PZAJPILZRFPYJJ-SRVKXCTJSA-N His-Ser-Leu Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(O)=O PZAJPILZRFPYJJ-SRVKXCTJSA-N 0.000 description 1
- 208000017662 Hodgkin disease lymphocyte depletion type stage unspecified Diseases 0.000 description 1
- 229910052689 Holmium Inorganic materials 0.000 description 1
- 101000745891 Homo sapiens Cytochrome P450 26A1 Proteins 0.000 description 1
- 101000726355 Homo sapiens Cytochrome c Proteins 0.000 description 1
- 101001060274 Homo sapiens Fibroblast growth factor 4 Proteins 0.000 description 1
- 101001011906 Homo sapiens Matrix metalloproteinase-14 Proteins 0.000 description 1
- 101100082597 Homo sapiens PDCD6IP gene Proteins 0.000 description 1
- 241000598436 Human T-cell lymphotropic virus Species 0.000 description 1
- 206010020460 Human T-cell lymphotropic virus type I infection Diseases 0.000 description 1
- 241000714260 Human T-lymphotropic virus 1 Species 0.000 description 1
- 241000714259 Human T-lymphotropic virus 2 Species 0.000 description 1
- 241000701024 Human betaherpesvirus 5 Species 0.000 description 1
- 241000701044 Human gammaherpesvirus 4 Species 0.000 description 1
- 108700020134 Human immunodeficiency virus 1 nef Proteins 0.000 description 1
- 108700003968 Human immunodeficiency virus 1 tat peptide (49-57) Proteins 0.000 description 1
- 241000342334 Human metapneumovirus Species 0.000 description 1
- 241000702617 Human parvovirus B19 Species 0.000 description 1
- 241000243251 Hydra Species 0.000 description 1
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 1
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 1
- 229920001479 Hydroxyethyl methyl cellulose Polymers 0.000 description 1
- PMMYEEVYMWASQN-DMTCNVIQSA-N Hydroxyproline Chemical compound O[C@H]1CN[C@H](C(O)=O)C1 PMMYEEVYMWASQN-DMTCNVIQSA-N 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 208000037147 Hypercalcaemia Diseases 0.000 description 1
- 206010048643 Hypereosinophilic syndrome Diseases 0.000 description 1
- JDAWAWXGAUZPNJ-ZPFDUUQYSA-N Ile-Glu-Arg Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)N JDAWAWXGAUZPNJ-ZPFDUUQYSA-N 0.000 description 1
- GVKKVHNRTUFCCE-BJDJZHNGSA-N Ile-Leu-Ser Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)O)N GVKKVHNRTUFCCE-BJDJZHNGSA-N 0.000 description 1
- VEPIBPGLTLPBDW-URLPEUOOSA-N Ile-Phe-Thr Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)O)C(=O)O)N VEPIBPGLTLPBDW-URLPEUOOSA-N 0.000 description 1
- CAHCWMVNBZJVAW-NAKRPEOUSA-N Ile-Pro-Ser Chemical compound CC[C@H](C)[C@@H](C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(=O)O)N CAHCWMVNBZJVAW-NAKRPEOUSA-N 0.000 description 1
- 108010021625 Immunoglobulin Fragments Proteins 0.000 description 1
- 102000008394 Immunoglobulin Fragments Human genes 0.000 description 1
- 206010062016 Immunosuppression Diseases 0.000 description 1
- 241000712431 Influenza A virus Species 0.000 description 1
- UGQMRVRMYYASKQ-KQYNXXCUSA-N Inosine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C2=NC=NC(O)=C2N=C1 UGQMRVRMYYASKQ-KQYNXXCUSA-N 0.000 description 1
- 102100034349 Integrase Human genes 0.000 description 1
- 108010079944 Interferon-alpha2b Proteins 0.000 description 1
- 108010063738 Interleukins Proteins 0.000 description 1
- 102000015696 Interleukins Human genes 0.000 description 1
- 206010023256 Juvenile melanoma benign Diseases 0.000 description 1
- 108010038142 KAI 9803 Proteins 0.000 description 1
- 208000007766 Kaposi sarcoma Diseases 0.000 description 1
- RFSMUFRPPYDYRD-CALCHBBNSA-N Ku-0063794 Chemical compound C1=C(CO)C(OC)=CC=C1C1=CC=C(C(=NC(=N2)N3C[C@@H](C)O[C@@H](C)C3)N3CCOCC3)C2=N1 RFSMUFRPPYDYRD-CALCHBBNSA-N 0.000 description 1
- CZWARROQQFCFJB-UHFFFAOYSA-N L-2-Amino-5-hydroxypentanoic acid Chemical compound OC(=O)C(N)CCCO CZWARROQQFCFJB-UHFFFAOYSA-N 0.000 description 1
- SNDPXSYFESPGGJ-BYPYZUCNSA-N L-2-aminopentanoic acid Chemical compound CCC[C@H](N)C(O)=O SNDPXSYFESPGGJ-BYPYZUCNSA-N 0.000 description 1
- FFEARJCKVFRZRR-UHFFFAOYSA-N L-Methionine Natural products CSCCC(N)C(O)=O FFEARJCKVFRZRR-UHFFFAOYSA-N 0.000 description 1
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 description 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
- RHGKLRLOHDJJDR-BYPYZUCNSA-N L-citrulline Chemical compound NC(=O)NCCC[C@H]([NH3+])C([O-])=O RHGKLRLOHDJJDR-BYPYZUCNSA-N 0.000 description 1
- UKAUYVFTDYCKQA-VKHMYHEASA-N L-homoserine Chemical compound OC(=O)[C@@H](N)CCO UKAUYVFTDYCKQA-VKHMYHEASA-N 0.000 description 1
- 125000001176 L-lysyl group Chemical group [H]N([H])[C@]([H])(C(=O)[*])C([H])([H])C([H])([H])C([H])([H])C(N([H])[H])([H])[H] 0.000 description 1
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 1
- 229930195722 L-methionine Natural products 0.000 description 1
- SNDPXSYFESPGGJ-UHFFFAOYSA-N L-norVal-OH Natural products CCCC(N)C(O)=O SNDPXSYFESPGGJ-UHFFFAOYSA-N 0.000 description 1
- LRQKBLKVPFOOQJ-YFKPBYRVSA-N L-norleucine Chemical compound CCCC[C@H]([NH3+])C([O-])=O LRQKBLKVPFOOQJ-YFKPBYRVSA-N 0.000 description 1
- 239000002118 L01XE12 - Vandetanib Substances 0.000 description 1
- UIARLYUEJFELEN-LROUJFHJSA-N LSM-1231 Chemical compound C12=C3N4C5=CC=CC=C5C3=C3C(=O)NCC3=C2C2=CC=CC=C2N1[C@]1(C)[C@](CO)(O)C[C@H]4O1 UIARLYUEJFELEN-LROUJFHJSA-N 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- 206010023927 Lassa fever Diseases 0.000 description 1
- 241000713666 Lentivirus Species 0.000 description 1
- VIWUBXKCYJGNCL-SRVKXCTJSA-N Leu-Asn-His Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@H](C(O)=O)CC1=CN=CN1 VIWUBXKCYJGNCL-SRVKXCTJSA-N 0.000 description 1
- WRLPVDVHNWSSCL-MELADBBJSA-N Leu-His-Pro Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)N2CCC[C@@H]2C(=O)O)N WRLPVDVHNWSSCL-MELADBBJSA-N 0.000 description 1
- KUIDCYNIEJBZBU-AJNGGQMLSA-N Leu-Ile-Leu Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(C)C)C(O)=O KUIDCYNIEJBZBU-AJNGGQMLSA-N 0.000 description 1
- DSFYPIUSAMSERP-IHRRRGAJSA-N Leu-Leu-Arg Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(O)=O)CCCN=C(N)N DSFYPIUSAMSERP-IHRRRGAJSA-N 0.000 description 1
- KYIIALJHAOIAHF-KKUMJFAQSA-N Leu-Leu-His Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(O)=O)CC1=CN=CN1 KYIIALJHAOIAHF-KKUMJFAQSA-N 0.000 description 1
- BGZCJDGBBUUBHA-KKUMJFAQSA-N Leu-Lys-Leu Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(O)=O BGZCJDGBBUUBHA-KKUMJFAQSA-N 0.000 description 1
- KWLWZYMNUZJKMZ-IHRRRGAJSA-N Leu-Pro-Leu Chemical compound CC(C)C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(C)C)C(O)=O KWLWZYMNUZJKMZ-IHRRRGAJSA-N 0.000 description 1
- KLSUAWUZBMAZCL-RHYQMDGZSA-N Leu-Thr-Pro Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1CCC[C@H]1C(O)=O KLSUAWUZBMAZCL-RHYQMDGZSA-N 0.000 description 1
- IDGRADDMTTWOQC-WDSOQIARSA-N Leu-Trp-Arg Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O IDGRADDMTTWOQC-WDSOQIARSA-N 0.000 description 1
- FDBTVENULFNTAL-XQQFMLRXSA-N Leu-Val-Pro Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)O)N FDBTVENULFNTAL-XQQFMLRXSA-N 0.000 description 1
- 206010024305 Leukaemia monocytic Diseases 0.000 description 1
- 239000000232 Lipid Bilayer Substances 0.000 description 1
- 206010024612 Lipoma Diseases 0.000 description 1
- 108090001030 Lipoproteins Proteins 0.000 description 1
- 102000004895 Lipoproteins Human genes 0.000 description 1
- GQYIWUVLTXOXAJ-UHFFFAOYSA-N Lomustine Chemical compound ClCCN(N=O)C(=O)NC1CCCCC1 GQYIWUVLTXOXAJ-UHFFFAOYSA-N 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 229910052765 Lutetium Inorganic materials 0.000 description 1
- 102000004317 Lyases Human genes 0.000 description 1
- 108090000856 Lyases Proteins 0.000 description 1
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 description 1
- WSXTWLJHTLRFLW-SRVKXCTJSA-N Lys-Ala-Lys Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCN)C(O)=O WSXTWLJHTLRFLW-SRVKXCTJSA-N 0.000 description 1
- ALSRJRIWBNENFY-DCAQKATOSA-N Lys-Arg-Asn Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(N)=O)C(O)=O ALSRJRIWBNENFY-DCAQKATOSA-N 0.000 description 1
- DKTNGXVSCZULPO-YUMQZZPRSA-N Lys-Gly-Cys Chemical compound NCCCC[C@H](N)C(=O)NCC(=O)N[C@@H](CS)C(O)=O DKTNGXVSCZULPO-YUMQZZPRSA-N 0.000 description 1
- NKKFVJRLCCUJNA-QWRGUYRKSA-N Lys-Gly-Lys Chemical compound NCCCC[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CCCCN NKKFVJRLCCUJNA-QWRGUYRKSA-N 0.000 description 1
- GFWLIJDQILOEPP-HSCHXYMDSA-N Lys-Ile-Trp Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)O)NC(=O)[C@H](CCCCN)N GFWLIJDQILOEPP-HSCHXYMDSA-N 0.000 description 1
- HVAUKHLDSDDROB-KKUMJFAQSA-N Lys-Lys-Leu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(O)=O HVAUKHLDSDDROB-KKUMJFAQSA-N 0.000 description 1
- MEQLGHAMAUPOSJ-DCAQKATOSA-N Lys-Ser-Val Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O MEQLGHAMAUPOSJ-DCAQKATOSA-N 0.000 description 1
- ZVZRQKJOQQAFCF-ULQDDVLXSA-N Lys-Tyr-Arg Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O ZVZRQKJOQQAFCF-ULQDDVLXSA-N 0.000 description 1
- 229940124528 MK-2048 Drugs 0.000 description 1
- 229940124640 MK-2206 Drugs 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- PEEHTFAAVSWFBL-UHFFFAOYSA-N Maleimide Chemical compound O=C1NC(=O)C=C1 PEEHTFAAVSWFBL-UHFFFAOYSA-N 0.000 description 1
- 102100030216 Matrix metalloproteinase-14 Human genes 0.000 description 1
- 208000007054 Medullary Carcinoma Diseases 0.000 description 1
- 208000000172 Medulloblastoma Diseases 0.000 description 1
- 208000035490 Megakaryoblastic Acute Leukemia Diseases 0.000 description 1
- 244000246386 Mentha pulegium Species 0.000 description 1
- 235000016257 Mentha pulegium Nutrition 0.000 description 1
- 235000004357 Mentha x piperita Nutrition 0.000 description 1
- 206010027406 Mesothelioma Diseases 0.000 description 1
- YRAWWKUTNBILNT-FXQIFTODSA-N Met-Ala-Ala Chemical compound CSCC[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(O)=O YRAWWKUTNBILNT-FXQIFTODSA-N 0.000 description 1
- HSJIGJRZYUADSS-IHRRRGAJSA-N Met-Lys-Leu Chemical compound [H]N[C@@H](CCSC)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(O)=O HSJIGJRZYUADSS-IHRRRGAJSA-N 0.000 description 1
- GGXZOTSDJJTDGB-GUBZILKMSA-N Met-Ser-Val Chemical compound [H]N[C@@H](CCSC)C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O GGXZOTSDJJTDGB-GUBZILKMSA-N 0.000 description 1
- UYDDNEYNGGSTDW-OYDLWJJNSA-N Met-Trp-Trp Chemical compound CSCC[C@@H](C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)N[C@@H](CC3=CNC4=CC=CC=C43)C(=O)O)N UYDDNEYNGGSTDW-OYDLWJJNSA-N 0.000 description 1
- 108700011259 MicroRNAs Proteins 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 229930192392 Mitomycin Natural products 0.000 description 1
- 108010006519 Molecular Chaperones Proteins 0.000 description 1
- KLPWJLBORRMFGK-UHFFFAOYSA-N Molindone Chemical compound O=C1C=2C(CC)=C(C)NC=2CCC1CN1CCOCC1 KLPWJLBORRMFGK-UHFFFAOYSA-N 0.000 description 1
- ZOKXTWBITQBERF-UHFFFAOYSA-N Molybdenum Chemical compound [Mo] ZOKXTWBITQBERF-UHFFFAOYSA-N 0.000 description 1
- 208000035489 Monocytic Acute Leukemia Diseases 0.000 description 1
- 206010057269 Mucoepidermoid carcinoma Diseases 0.000 description 1
- 208000034578 Multiple myelomas Diseases 0.000 description 1
- OUSFTKFNBAZUKL-UHFFFAOYSA-N N-(5-{[(5-tert-butyl-1,3-oxazol-2-yl)methyl]sulfanyl}-1,3-thiazol-2-yl)piperidine-4-carboxamide Chemical compound O1C(C(C)(C)C)=CN=C1CSC(S1)=CN=C1NC(=O)C1CCNCC1 OUSFTKFNBAZUKL-UHFFFAOYSA-N 0.000 description 1
- WUGMRIBZSVSJNP-UHFFFAOYSA-N N-L-alanyl-L-tryptophan Natural products C1=CC=C2C(CC(NC(=O)C(N)C)C(O)=O)=CNC2=C1 WUGMRIBZSVSJNP-UHFFFAOYSA-N 0.000 description 1
- WYBVBIHNJWOLCJ-UHFFFAOYSA-N N-L-arginyl-L-leucine Natural products CC(C)CC(C(O)=O)NC(=O)C(N)CCCN=C(N)N WYBVBIHNJWOLCJ-UHFFFAOYSA-N 0.000 description 1
- LKJPYSCBVHEWIU-UHFFFAOYSA-N N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)sulfonyl]-2-hydroxy-2-methylpropanamide Chemical compound C=1C=C(C#N)C(C(F)(F)F)=CC=1NC(=O)C(O)(C)CS(=O)(=O)C1=CC=C(F)C=C1 LKJPYSCBVHEWIU-UHFFFAOYSA-N 0.000 description 1
- BQVUABVGYYSDCJ-UHFFFAOYSA-N Nalpha-L-Leucyl-L-tryptophan Natural products C1=CC=C2C(CC(NC(=O)C(N)CC(C)C)C(O)=O)=CNC2=C1 BQVUABVGYYSDCJ-UHFFFAOYSA-N 0.000 description 1
- RHGKLRLOHDJJDR-UHFFFAOYSA-N Ndelta-carbamoyl-DL-ornithine Natural products OC(=O)C(N)CCCNC(N)=O RHGKLRLOHDJJDR-UHFFFAOYSA-N 0.000 description 1
- DDUHZTYCFQRHIY-UHFFFAOYSA-N Negwer: 6874 Natural products COC1=CC(=O)CC(C)C11C(=O)C(C(OC)=CC(OC)=C2Cl)=C2O1 DDUHZTYCFQRHIY-UHFFFAOYSA-N 0.000 description 1
- 229910052779 Neodymium Inorganic materials 0.000 description 1
- 206010029488 Nodular melanoma Diseases 0.000 description 1
- 102100036206 Nucleoredoxin Human genes 0.000 description 1
- 229940122313 Nucleoside reverse transcriptase inhibitor Drugs 0.000 description 1
- 206010030155 Oesophageal carcinoma Diseases 0.000 description 1
- 108091034117 Oligonucleotide Proteins 0.000 description 1
- AHLPHDHHMVZTML-UHFFFAOYSA-N Orn-delta-NH2 Natural products NCCCC(N)C(O)=O AHLPHDHHMVZTML-UHFFFAOYSA-N 0.000 description 1
- UTJLXEIPEHZYQJ-UHFFFAOYSA-N Ornithine Natural products OC(=O)C(C)CCCN UTJLXEIPEHZYQJ-UHFFFAOYSA-N 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 239000004100 Oxytetracycline Substances 0.000 description 1
- 239000012661 PARP inhibitor Substances 0.000 description 1
- TUVCWJQQGGETHL-UHFFFAOYSA-N PI-103 Chemical compound OC1=CC=CC(C=2N=C3C4=CC=CN=C4OC3=C(N3CCOCC3)N=2)=C1 TUVCWJQQGGETHL-UHFFFAOYSA-N 0.000 description 1
- 239000012828 PI3K inhibitor Substances 0.000 description 1
- 208000037273 Pathologic Processes Diseases 0.000 description 1
- JNTOCHDNEULJHD-UHFFFAOYSA-N Penciclovir Chemical compound N1C(N)=NC(=O)C2=C1N(CCC(CO)CO)C=N2 JNTOCHDNEULJHD-UHFFFAOYSA-N 0.000 description 1
- 241000150350 Peribunyaviridae Species 0.000 description 1
- UMKYAYXCMYYNHI-AVGNSLFASA-N Phe-Gln-Asn Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CC(=O)N)C(=O)O)N UMKYAYXCMYYNHI-AVGNSLFASA-N 0.000 description 1
- NKLDZIPTGKBDBB-HTUGSXCWSA-N Phe-Gln-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CC1=CC=CC=C1)N)O NKLDZIPTGKBDBB-HTUGSXCWSA-N 0.000 description 1
- WLYPRKLMRIYGPP-JYJNAYRXSA-N Phe-Lys-Glu Chemical compound OC(=O)CC[C@@H](C(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)CC1=CC=CC=C1 WLYPRKLMRIYGPP-JYJNAYRXSA-N 0.000 description 1
- 241001662443 Phemeranthus parviflorus Species 0.000 description 1
- 241000709664 Picornaviridae Species 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- 241000711904 Pneumoviridae Species 0.000 description 1
- 241000711902 Pneumovirus Species 0.000 description 1
- 229940121906 Poly ADP ribose polymerase inhibitor Drugs 0.000 description 1
- 229920000954 Polyglycolide Polymers 0.000 description 1
- 108010039918 Polylysine Proteins 0.000 description 1
- 101710102873 Polymerase basic protein 2 Proteins 0.000 description 1
- 229940123066 Polymerase inhibitor Drugs 0.000 description 1
- 229910052777 Praseodymium Inorganic materials 0.000 description 1
- 206010049422 Precancerous skin lesion Diseases 0.000 description 1
- 102000029797 Prion Human genes 0.000 description 1
- 108091000054 Prion Proteins 0.000 description 1
- DZZCICYRSZASNF-FXQIFTODSA-N Pro-Ala-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H]1CCCN1 DZZCICYRSZASNF-FXQIFTODSA-N 0.000 description 1
- JLMZKEQFMVORMA-SRVKXCTJSA-N Pro-Pro-Arg Chemical compound NC(N)=NCCC[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@H]1NCCC1 JLMZKEQFMVORMA-SRVKXCTJSA-N 0.000 description 1
- QAAYIXYLEMRULP-SRVKXCTJSA-N Pro-Pro-Met Chemical compound CSCC[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@H]1NCCC1 QAAYIXYLEMRULP-SRVKXCTJSA-N 0.000 description 1
- QMABBZHZMDXHKU-FKBYEOEOSA-N Pro-Tyr-Trp Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(O)=O QMABBZHZMDXHKU-FKBYEOEOSA-N 0.000 description 1
- 208000033826 Promyelocytic Acute Leukemia Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 101710149951 Protein Tat Proteins 0.000 description 1
- 101710188315 Protein X Proteins 0.000 description 1
- 241000125945 Protoparvovirus Species 0.000 description 1
- 241000508269 Psidium Species 0.000 description 1
- 108091030071 RNAI Proteins 0.000 description 1
- 108020004511 Recombinant DNA Proteins 0.000 description 1
- 208000006265 Renal cell carcinoma Diseases 0.000 description 1
- IWUCXVSUMQZMFG-AFCXAGJDSA-N Ribavirin Chemical compound N1=C(C(=O)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 IWUCXVSUMQZMFG-AFCXAGJDSA-N 0.000 description 1
- NCDNCNXCDXHOMX-UHFFFAOYSA-N Ritonavir Natural products C=1C=CC=CC=1CC(NC(=O)OCC=1SC=NC=1)C(O)CC(CC=1C=CC=CC=1)NC(=O)C(C(C)C)NC(=O)N(C)CC1=CSC(C(C)C)=N1 NCDNCNXCDXHOMX-UHFFFAOYSA-N 0.000 description 1
- 241000702670 Rotavirus Species 0.000 description 1
- 108010040181 SF 1126 Proteins 0.000 description 1
- 201000001542 Schneiderian carcinoma Diseases 0.000 description 1
- HQTKVSCNCDLXSX-BQBZGAKWSA-N Ser-Arg-Gly Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(O)=O HQTKVSCNCDLXSX-BQBZGAKWSA-N 0.000 description 1
- QFBNNYNWKYKVJO-DCAQKATOSA-N Ser-Arg-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CO)CCCN=C(N)N QFBNNYNWKYKVJO-DCAQKATOSA-N 0.000 description 1
- BQWCDDAISCPDQV-XHNCKOQMSA-N Ser-Gln-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CO)N)C(=O)O BQWCDDAISCPDQV-XHNCKOQMSA-N 0.000 description 1
- FYUIFUJFNCLUIX-XVYDVKMFSA-N Ser-His-Ala Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](C)C(O)=O FYUIFUJFNCLUIX-XVYDVKMFSA-N 0.000 description 1
- YIUWWXVTYLANCJ-NAKRPEOUSA-N Ser-Ile-Arg Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O YIUWWXVTYLANCJ-NAKRPEOUSA-N 0.000 description 1
- QYSFWUIXDFJUDW-DCAQKATOSA-N Ser-Leu-Arg Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O QYSFWUIXDFJUDW-DCAQKATOSA-N 0.000 description 1
- VZQRNAYURWAEFE-KKUMJFAQSA-N Ser-Leu-Phe Chemical compound OC[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 VZQRNAYURWAEFE-KKUMJFAQSA-N 0.000 description 1
- SRKMDKACHDVPMD-SRVKXCTJSA-N Ser-Lys-His Chemical compound C1=C(NC=N1)C[C@@H](C(=O)O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)N SRKMDKACHDVPMD-SRVKXCTJSA-N 0.000 description 1
- ASGYVPAVFNDZMA-GUBZILKMSA-N Ser-Met-Val Chemical compound CC(C)[C@@H](C(=O)O)NC(=O)[C@H](CCSC)NC(=O)[C@H](CO)N ASGYVPAVFNDZMA-GUBZILKMSA-N 0.000 description 1
- ADJDNJCSPNFFPI-FXQIFTODSA-N Ser-Pro-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CO ADJDNJCSPNFFPI-FXQIFTODSA-N 0.000 description 1
- FKYWFUYPVKLJLP-DCAQKATOSA-N Ser-Pro-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CO FKYWFUYPVKLJLP-DCAQKATOSA-N 0.000 description 1
- KQNDIKOYWZTZIX-FXQIFTODSA-N Ser-Ser-Arg Chemical compound OC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CCCNC(N)=N KQNDIKOYWZTZIX-FXQIFTODSA-N 0.000 description 1
- WMZVVNLPHFSUPA-BPUTZDHNSA-N Ser-Trp-Arg Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@H](CO)N)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O)=CNC2=C1 WMZVVNLPHFSUPA-BPUTZDHNSA-N 0.000 description 1
- 108010071390 Serum Albumin Proteins 0.000 description 1
- 102000007562 Serum Albumin Human genes 0.000 description 1
- 229920001800 Shellac Polymers 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
- 101800001707 Spacer peptide Proteins 0.000 description 1
- XNKLLVCARDGLGL-JGVFFNPUSA-N Stavudine Chemical compound O=C1NC(=O)C(C)=CN1[C@H]1C=C[C@@H](CO)O1 XNKLLVCARDGLGL-JGVFFNPUSA-N 0.000 description 1
- ZSJLQEPLLKMAKR-UHFFFAOYSA-N Streptozotocin Natural products O=NN(C)C(=O)NC1C(O)OC(CO)C(O)C1O ZSJLQEPLLKMAKR-UHFFFAOYSA-N 0.000 description 1
- 108700005078 Synthetic Genes Proteins 0.000 description 1
- 229920001963 Synthetic biodegradable polymer Polymers 0.000 description 1
- 108091008874 T cell receptors Proteins 0.000 description 1
- 102000016266 T-Cell Antigen Receptors Human genes 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- 239000006180 TBST buffer Substances 0.000 description 1
- CBPNZQVSJQDFBE-FUXHJELOSA-N Temsirolimus Chemical compound C1C[C@@H](OC(=O)C(C)(CO)CO)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 CBPNZQVSJQDFBE-FUXHJELOSA-N 0.000 description 1
- 229910052771 Terbium Inorganic materials 0.000 description 1
- 208000024313 Testicular Neoplasms Diseases 0.000 description 1
- 206010057644 Testis cancer Diseases 0.000 description 1
- 108700031126 Tetraspanins Proteins 0.000 description 1
- 102000043977 Tetraspanins Human genes 0.000 description 1
- FOCVUCIESVLUNU-UHFFFAOYSA-N Thiotepa Chemical compound C1CN1P(N1CC1)(=S)N1CC1 FOCVUCIESVLUNU-UHFFFAOYSA-N 0.000 description 1
- 229910052776 Thorium Inorganic materials 0.000 description 1
- IGROJMCBGRFRGI-YTLHQDLWSA-N Thr-Ala-Ala Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(O)=O IGROJMCBGRFRGI-YTLHQDLWSA-N 0.000 description 1
- XFTYVCHLARBHBQ-FOHZUACHSA-N Thr-Gly-Asn Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N[C@@H](CC(N)=O)C(O)=O XFTYVCHLARBHBQ-FOHZUACHSA-N 0.000 description 1
- NQVDGKYAUHTCME-QTKMDUPCSA-N Thr-His-Arg Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)N)O NQVDGKYAUHTCME-QTKMDUPCSA-N 0.000 description 1
- BQBCIBCLXBKYHW-CSMHCCOUSA-N Thr-Leu Chemical compound CC(C)C[C@@H](C([O-])=O)NC(=O)[C@@H]([NH3+])[C@@H](C)O BQBCIBCLXBKYHW-CSMHCCOUSA-N 0.000 description 1
- ODXKUIGEPAGKKV-KATARQTJSA-N Thr-Leu-Cys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CS)C(=O)O)N)O ODXKUIGEPAGKKV-KATARQTJSA-N 0.000 description 1
- ISLDRLHVPXABBC-IEGACIPQSA-N Thr-Leu-Trp Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(O)=O ISLDRLHVPXABBC-IEGACIPQSA-N 0.000 description 1
- VEIKMWOMUYMMMK-FCLVOEFKSA-N Thr-Phe-Phe Chemical compound C([C@H](NC(=O)[C@@H](N)[C@H](O)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CC=CC=C1 VEIKMWOMUYMMMK-FCLVOEFKSA-N 0.000 description 1
- DNCUODYZAMHLCV-XGEHTFHBSA-N Thr-Pro-Cys Chemical compound C[C@H]([C@@H](C(=O)N1CCC[C@H]1C(=O)N[C@@H](CS)C(=O)O)N)O DNCUODYZAMHLCV-XGEHTFHBSA-N 0.000 description 1
- IJKNKFJZOJCKRR-GBALPHGKSA-N Thr-Trp-Ser Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@@H](N)[C@H](O)C)C(=O)N[C@@H](CO)C(O)=O)=CNC2=C1 IJKNKFJZOJCKRR-GBALPHGKSA-N 0.000 description 1
- 229910052775 Thulium Inorganic materials 0.000 description 1
- 208000024770 Thyroid neoplasm Diseases 0.000 description 1
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 1
- SUJUHGSWHZTSEU-UHFFFAOYSA-N Tipranavir Natural products C1C(O)=C(C(CC)C=2C=C(NS(=O)(=O)C=3N=CC(=CC=3)C(F)(F)F)C=CC=2)C(=O)OC1(CCC)CCC1=CC=CC=C1 SUJUHGSWHZTSEU-UHFFFAOYSA-N 0.000 description 1
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 1
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 description 1
- IWEQQRMGNVVKQW-OQKDUQJOSA-N Toremifene citrate Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O.C1=CC(OCCN(C)C)=CC=C1C(\C=1C=CC=CC=1)=C(\CCCl)C1=CC=CC=C1 IWEQQRMGNVVKQW-OQKDUQJOSA-N 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 102000004338 Transferrin Human genes 0.000 description 1
- 108090000901 Transferrin Proteins 0.000 description 1
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 description 1
- DFBIRQPKNDILPW-CIVMWXNOSA-N Triptolide Chemical compound O=C1OCC([C@@H]2C3)=C1CC[C@]2(C)[C@]12O[C@H]1[C@@H]1O[C@]1(C(C)C)[C@@H](O)[C@]21[C@H]3O1 DFBIRQPKNDILPW-CIVMWXNOSA-N 0.000 description 1
- UUIYFDAWNBSWPG-IHPCNDPISA-N Trp-Lys-Lys Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)O)N UUIYFDAWNBSWPG-IHPCNDPISA-N 0.000 description 1
- SNWIAPVRCNYFNI-SZMVWBNQSA-N Trp-Met-Arg Chemical compound CSCC[C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)NC(=O)[C@H](CC1=CNC2=CC=CC=C21)N SNWIAPVRCNYFNI-SZMVWBNQSA-N 0.000 description 1
- BOESUSAIMQGVJD-RYQLBKOJSA-N Trp-Met-Pro Chemical compound CSCC[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CC2=CNC3=CC=CC=C32)N BOESUSAIMQGVJD-RYQLBKOJSA-N 0.000 description 1
- GEGYPBOPIGNZIF-CWRNSKLLSA-N Trp-Ser-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CO)NC(=O)[C@H](CC2=CNC3=CC=CC=C32)N)C(=O)O GEGYPBOPIGNZIF-CWRNSKLLSA-N 0.000 description 1
- UBAQSAUDKMIEQZ-QWRGUYRKSA-N Tyr-Gln Chemical compound NC(=O)CC[C@@H](C(O)=O)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 UBAQSAUDKMIEQZ-QWRGUYRKSA-N 0.000 description 1
- HIINQLBHPIQYHN-JTQLQIEISA-N Tyr-Gly-Gly Chemical compound OC(=O)CNC(=O)CNC(=O)[C@@H](N)CC1=CC=C(O)C=C1 HIINQLBHPIQYHN-JTQLQIEISA-N 0.000 description 1
- JAGGEZACYAAMIL-CQDKDKBSSA-N Tyr-Lys-Ala Chemical compound C[C@@H](C(=O)O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC1=CC=C(C=C1)O)N JAGGEZACYAAMIL-CQDKDKBSSA-N 0.000 description 1
- AUZADXNWQMBZOO-JYJNAYRXSA-N Tyr-Pro-Arg Chemical compound C([C@H](N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O)C1=CC=C(O)C=C1 AUZADXNWQMBZOO-JYJNAYRXSA-N 0.000 description 1
- NZBSVMQZQMEUHI-WZLNRYEVSA-N Tyr-Thr-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)N NZBSVMQZQMEUHI-WZLNRYEVSA-N 0.000 description 1
- DVEXZJFMOKTQEZ-JYFOCSDGSA-N U0126 Chemical compound C=1C=CC=C(N)C=1SC(\N)=C(/C#N)\C(\C#N)=C(/N)SC1=CC=CC=C1N DVEXZJFMOKTQEZ-JYFOCSDGSA-N 0.000 description 1
- 108090000848 Ubiquitin Proteins 0.000 description 1
- 102000044159 Ubiquitin Human genes 0.000 description 1
- 229910052770 Uranium Inorganic materials 0.000 description 1
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 1
- 241000700618 Vaccinia virus Species 0.000 description 1
- XTDDIVQWDXMRJL-IHRRRGAJSA-N Val-Leu-His Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)NC(=O)[C@H](C(C)C)N XTDDIVQWDXMRJL-IHRRRGAJSA-N 0.000 description 1
- JKHXYJKMNSSFFL-IUCAKERBSA-N Val-Lys Chemical compound CC(C)[C@H](N)C(=O)N[C@H](C(O)=O)CCCCN JKHXYJKMNSSFFL-IUCAKERBSA-N 0.000 description 1
- YTNGABPUXFEOGU-SRVKXCTJSA-N Val-Pro-Arg Chemical compound CC(C)[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCN=C(N)N)C(O)=O YTNGABPUXFEOGU-SRVKXCTJSA-N 0.000 description 1
- AYHNXCJKBLYVOA-KSZLIROESA-N Val-Trp-Pro Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)N3CCC[C@@H]3C(=O)O)N AYHNXCJKBLYVOA-KSZLIROESA-N 0.000 description 1
- HDOVUKNUBWVHOX-QMMMGPOBSA-N Valacyclovir Chemical compound N1C(N)=NC(=O)C2=C1N(COCCOC(=O)[C@@H](N)C(C)C)C=N2 HDOVUKNUBWVHOX-QMMMGPOBSA-N 0.000 description 1
- JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 description 1
- 108700005077 Viral Genes Proteins 0.000 description 1
- 206010047741 Vulval cancer Diseases 0.000 description 1
- 208000033559 Waldenström macroglobulinemia Diseases 0.000 description 1
- 239000005862 Whey Substances 0.000 description 1
- 108010046377 Whey Proteins Proteins 0.000 description 1
- 102000007544 Whey Proteins Human genes 0.000 description 1
- 102100036976 X-ray repair cross-complementing protein 6 Human genes 0.000 description 1
- 101710124907 X-ray repair cross-complementing protein 6 Proteins 0.000 description 1
- 108010017758 YU101 Proteins 0.000 description 1
- 208000012018 Yolk sac tumor Diseases 0.000 description 1
- 229910052769 Ytterbium Inorganic materials 0.000 description 1
- WREGKURFCTUGRC-POYBYMJQSA-N Zalcitabine Chemical compound O=C1N=C(N)C=CN1[C@@H]1O[C@H](CO)CC1 WREGKURFCTUGRC-POYBYMJQSA-N 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- QCWXUUIWCKQGHC-UHFFFAOYSA-N Zirconium Chemical compound [Zr] QCWXUUIWCKQGHC-UHFFFAOYSA-N 0.000 description 1
- 229960004748 abacavir Drugs 0.000 description 1
- MCGSCOLBFJQGHM-SCZZXKLOSA-N abacavir Chemical compound C=12N=CN([C@H]3C=C[C@@H](CO)C3)C2=NC(N)=NC=1NC1CC1 MCGSCOLBFJQGHM-SCZZXKLOSA-N 0.000 description 1
- 229960000853 abiraterone Drugs 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 229940028652 abraxane Drugs 0.000 description 1
- 239000002250 absorbent Substances 0.000 description 1
- 230000002745 absorbent Effects 0.000 description 1
- 239000003070 absorption delaying agent Substances 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 1
- 229960004150 aciclovir Drugs 0.000 description 1
- MKUXAQIIEYXACX-UHFFFAOYSA-N aciclovir Chemical compound N1C(N)=NC(=O)C2=C1N(COCCO)C=N2 MKUXAQIIEYXACX-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 208000006336 acinar cell carcinoma Diseases 0.000 description 1
- 206010000496 acne Diseases 0.000 description 1
- 125000000641 acridinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3C=C12)* 0.000 description 1
- 229910052768 actinide Inorganic materials 0.000 description 1
- 150000001255 actinides Chemical class 0.000 description 1
- RJURFGZVJUQBHK-IIXSONLDSA-N actinomycin D Chemical compound C[C@H]1OC(=O)[C@H](C(C)C)N(C)C(=O)CN(C)C(=O)[C@@H]2CCCN2C(=O)[C@@H](C(C)C)NC(=O)[C@H]1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)N[C@@H]4C(=O)N[C@@H](C(N5CCC[C@H]5C(=O)N(C)CC(=O)N(C)[C@@H](C(C)C)C(=O)O[C@@H]4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-IIXSONLDSA-N 0.000 description 1
- RJURFGZVJUQBHK-UHFFFAOYSA-N actinomycin-C1 Natural products CC1OC(=O)C(C(C)C)N(C)C(=O)CN(C)C(=O)C2CCCN2C(=O)C(C(C)C)NC(=O)C1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)NC4C(=O)NC(C(N5CCCC5C(=O)N(C)CC(=O)N(C)C(C(C)C)C(=O)OC4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-UHFFFAOYSA-N 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 208000020700 acute megakaryocytic leukemia Diseases 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 229960001997 adefovir Drugs 0.000 description 1
- 229960003205 adefovir dipivoxil Drugs 0.000 description 1
- 210000002534 adenoid Anatomy 0.000 description 1
- 208000002517 adenoid cystic carcinoma Diseases 0.000 description 1
- 229960005305 adenosine Drugs 0.000 description 1
- WNLRTRBMVRJNCN-UHFFFAOYSA-L adipate(2-) Chemical compound [O-]C(=O)CCCCC([O-])=O WNLRTRBMVRJNCN-UHFFFAOYSA-L 0.000 description 1
- 201000002454 adrenal cortex cancer Diseases 0.000 description 1
- 208000020990 adrenal cortex carcinoma Diseases 0.000 description 1
- 208000007128 adrenocortical carcinoma Diseases 0.000 description 1
- 229940064305 adrucil Drugs 0.000 description 1
- 239000003463 adsorbent Substances 0.000 description 1
- 201000006966 adult T-cell leukemia Diseases 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- 108010056243 alanylalanine Proteins 0.000 description 1
- 108010044940 alanylglutamine Proteins 0.000 description 1
- 108010070944 alanylhistidine Proteins 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- GZCGUPFRVQAUEE-SLPGGIOYSA-N aldehydo-D-glucose Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O GZCGUPFRVQAUEE-SLPGGIOYSA-N 0.000 description 1
- 108700025316 aldesleukin Proteins 0.000 description 1
- HAXFWIACAGNFHA-UHFFFAOYSA-N aldrithiol Chemical compound C=1C=CC=NC=1SSC1=CC=CC=N1 HAXFWIACAGNFHA-UHFFFAOYSA-N 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 229940098174 alkeran Drugs 0.000 description 1
- SHGAZHPCJJPHSC-YCNIQYBTSA-N all-trans-retinoic acid Chemical compound OC(=O)\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-YCNIQYBTSA-N 0.000 description 1
- 230000000172 allergic effect Effects 0.000 description 1
- 229950010482 alpelisib Drugs 0.000 description 1
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 description 1
- WQZGKKKJIJFFOK-PHYPRBDBSA-N alpha-D-galactose Chemical compound OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@H]1O WQZGKKKJIJFFOK-PHYPRBDBSA-N 0.000 description 1
- 102000013529 alpha-Fetoproteins Human genes 0.000 description 1
- 108010026331 alpha-Fetoproteins Proteins 0.000 description 1
- AKNNEGZIBPJZJG-UHFFFAOYSA-N alpha-noscapine Natural products CN1CCC2=CC=3OCOC=3C(OC)=C2C1C1C2=CC=C(OC)C(OC)=C2C(=O)O1 AKNNEGZIBPJZJG-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229950010817 alvocidib Drugs 0.000 description 1
- BIIVYFLTOXDAOV-YVEFUNNKSA-N alvocidib Chemical compound O[C@@H]1CN(C)CC[C@@H]1C1=C(O)C=C(O)C2=C1OC(C=1C(=CC=CC=1)Cl)=CC2=O BIIVYFLTOXDAOV-YVEFUNNKSA-N 0.000 description 1
- 229960003805 amantadine Drugs 0.000 description 1
- DKNWSYNQZKUICI-UHFFFAOYSA-N amantadine Chemical compound C1C(C2)CC3CC2CC1(N)C3 DKNWSYNQZKUICI-UHFFFAOYSA-N 0.000 description 1
- 230000002707 ameloblastic effect Effects 0.000 description 1
- JKOQGQFVAUAYPM-UHFFFAOYSA-N amifostine Chemical compound NCCCNCCSP(O)(O)=O JKOQGQFVAUAYPM-UHFFFAOYSA-N 0.000 description 1
- 229960001097 amifostine Drugs 0.000 description 1
- 229960001830 amprenavir Drugs 0.000 description 1
- YMARZQAQMVYCKC-OEMFJLHTSA-N amprenavir Chemical compound C([C@@H]([C@H](O)CN(CC(C)C)S(=O)(=O)C=1C=CC(N)=CC=1)NC(=O)O[C@@H]1COCC1)C1=CC=CC=C1 YMARZQAQMVYCKC-OEMFJLHTSA-N 0.000 description 1
- 229960002932 anastrozole Drugs 0.000 description 1
- 229940004511 androxy Drugs 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 238000012653 anionic ring-opening polymerization Methods 0.000 description 1
- LJZJHELAFLRVSU-UHFFFAOYSA-N anthracene;phenanthrene Chemical compound C1=CC=CC2=CC3=CC=CC=C3C=C21.C1=CC=C2C3=CC=CC=C3C=CC2=C1 LJZJHELAFLRVSU-UHFFFAOYSA-N 0.000 description 1
- 230000001028 anti-proliverative effect Effects 0.000 description 1
- 230000000798 anti-retroviral effect Effects 0.000 description 1
- 230000010056 antibody-dependent cellular cytotoxicity Effects 0.000 description 1
- 210000000612 antigen-presenting cell Anatomy 0.000 description 1
- 229940111131 antiinflammatory and antirheumatic product propionic acid derivative Drugs 0.000 description 1
- 229910052787 antimony Inorganic materials 0.000 description 1
- WATWJIUSRGPENY-UHFFFAOYSA-N antimony atom Chemical compound [Sb] WATWJIUSRGPENY-UHFFFAOYSA-N 0.000 description 1
- 229940034982 antineoplastic agent Drugs 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 108010013835 arginine glutamate Proteins 0.000 description 1
- 108010068380 arginylarginine Proteins 0.000 description 1
- 108010062796 arginyllysine Proteins 0.000 description 1
- 229940078010 arimidex Drugs 0.000 description 1
- 229940087620 aromasin Drugs 0.000 description 1
- 229960004191 artemisinin Drugs 0.000 description 1
- BLUAFEHZUWYNDE-NNWCWBAJSA-N artemisinin Chemical compound C([C@](OO1)(C)O2)C[C@H]3[C@H](C)CC[C@@H]4[C@@]31[C@@H]2OC(=O)[C@@H]4C BLUAFEHZUWYNDE-NNWCWBAJSA-N 0.000 description 1
- 229930101531 artemisinin Natural products 0.000 description 1
- 108010084541 asialoorosomucoid Proteins 0.000 description 1
- 229960003272 asparaginase Drugs 0.000 description 1
- DCXYFEDJOCDNAF-UHFFFAOYSA-M asparaginate Chemical compound [O-]C(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-M 0.000 description 1
- 235000009582 asparagine Nutrition 0.000 description 1
- 229960001230 asparagine Drugs 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 244000309743 astrovirus Species 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- RRZXIRBKKLTSOM-XPNPUAGNSA-N avermectin B1a Chemical compound C1=C[C@H](C)[C@@H]([C@@H](C)CC)O[C@]11O[C@H](C\C=C(C)\[C@@H](O[C@@H]2O[C@@H](C)[C@H](O[C@@H]3O[C@@H](C)[C@H](O)[C@@H](OC)C3)[C@@H](OC)C2)[C@@H](C)\C=C\C=C/2[C@]3([C@H](C(=O)O4)C=C(C)[C@@H](O)[C@H]3OC\2)O)C[C@H]4C1 RRZXIRBKKLTSOM-XPNPUAGNSA-N 0.000 description 1
- 210000003719 b-lymphocyte Anatomy 0.000 description 1
- 230000003385 bacteriostatic effect Effects 0.000 description 1
- 229910052788 barium Inorganic materials 0.000 description 1
- DSAJWYNOEDNPEQ-UHFFFAOYSA-N barium atom Chemical compound [Ba] DSAJWYNOEDNPEQ-UHFFFAOYSA-N 0.000 description 1
- 239000007640 basal medium Substances 0.000 description 1
- 208000003373 basosquamous carcinoma Diseases 0.000 description 1
- 229960002707 bendamustine Drugs 0.000 description 1
- YTKUWDBFDASYHO-UHFFFAOYSA-N bendamustine Chemical compound ClCCN(CCCl)C1=CC=C2N(C)C(CCCC(O)=O)=NC2=C1 YTKUWDBFDASYHO-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 229960004217 benzyl alcohol Drugs 0.000 description 1
- WTOFYLAWDLQMBZ-LURJTMIESA-N beta(2-thienyl)alanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CS1 WTOFYLAWDLQMBZ-LURJTMIESA-N 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 229960002938 bexarotene Drugs 0.000 description 1
- 229940108502 bicnu Drugs 0.000 description 1
- 239000003833 bile salt Substances 0.000 description 1
- 229940093761 bile salts Drugs 0.000 description 1
- ACWZRVQXLIRSDF-UHFFFAOYSA-N binimetinib Chemical compound OCCONC(=O)C=1C=C2N(C)C=NC2=C(F)C=1NC1=CC=C(Br)C=C1F ACWZRVQXLIRSDF-UHFFFAOYSA-N 0.000 description 1
- 229920000249 biocompatible polymer Polymers 0.000 description 1
- 239000013060 biological fluid Substances 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 229910052797 bismuth Inorganic materials 0.000 description 1
- JCXGWMGPZLAOME-UHFFFAOYSA-N bismuth atom Chemical compound [Bi] JCXGWMGPZLAOME-UHFFFAOYSA-N 0.000 description 1
- 229960001561 bleomycin Drugs 0.000 description 1
- OYVAGSVQBOHSSS-UAPAGMARSA-O bleomycin A2 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C OYVAGSVQBOHSSS-UAPAGMARSA-O 0.000 description 1
- 229960000517 boceprevir Drugs 0.000 description 1
- LHHCSNFAOIFYRV-DOVBMPENSA-N boceprevir Chemical compound O=C([C@@H]1[C@@H]2[C@@H](C2(C)C)CN1C(=O)[C@@H](NC(=O)NC(C)(C)C)C(C)(C)C)NC(C(=O)C(N)=O)CC1CCC1 LHHCSNFAOIFYRV-DOVBMPENSA-N 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- 229910052796 boron Inorganic materials 0.000 description 1
- 229960003736 bosutinib Drugs 0.000 description 1
- UBPYILGKFZZVDX-UHFFFAOYSA-N bosutinib Chemical compound C1=C(Cl)C(OC)=CC(NC=2C3=CC(OC)=C(OCCCN4CCN(C)CC4)C=C3N=CC=2C#N)=C1Cl UBPYILGKFZZVDX-UHFFFAOYSA-N 0.000 description 1
- 201000009480 botryoid rhabdomyosarcoma Diseases 0.000 description 1
- 208000003362 bronchogenic carcinoma Diseases 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 229960002092 busulfan Drugs 0.000 description 1
- DQXBYHZEEUGOBF-UHFFFAOYSA-N but-3-enoic acid;ethene Chemical compound C=C.OC(=O)CC=C DQXBYHZEEUGOBF-UHFFFAOYSA-N 0.000 description 1
- 150000004648 butanoic acid derivatives Chemical class 0.000 description 1
- ZTQSAGDEMFDKMZ-UHFFFAOYSA-N butyric aldehyde Natural products CCCC=O ZTQSAGDEMFDKMZ-UHFFFAOYSA-N 0.000 description 1
- 229910052793 cadmium Inorganic materials 0.000 description 1
- BDOSMKKIYDKNTQ-UHFFFAOYSA-N cadmium atom Chemical compound [Cd] BDOSMKKIYDKNTQ-UHFFFAOYSA-N 0.000 description 1
- BQRGNLJZBFXNCZ-UHFFFAOYSA-N calcein am Chemical compound O1C(=O)C2=CC=CC=C2C21C1=CC(CN(CC(=O)OCOC(C)=O)CC(=O)OCOC(C)=O)=C(OC(C)=O)C=C1OC1=C2C=C(CN(CC(=O)OCOC(C)=O)CC(=O)OCOC(=O)C)C(OC(C)=O)=C1 BQRGNLJZBFXNCZ-UHFFFAOYSA-N 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 229940088954 camptosar Drugs 0.000 description 1
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical compound C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 description 1
- 229940127093 camptothecin Drugs 0.000 description 1
- 230000004611 cancer cell death Effects 0.000 description 1
- 230000009702 cancer cell proliferation Effects 0.000 description 1
- 230000005907 cancer growth Effects 0.000 description 1
- 150000001718 carbodiimides Chemical class 0.000 description 1
- 125000000837 carbohydrate group Chemical group 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 230000006315 carbonylation Effects 0.000 description 1
- 238000005810 carbonylation reaction Methods 0.000 description 1
- 229960004562 carboplatin Drugs 0.000 description 1
- 125000005392 carboxamide group Chemical group NC(=O)* 0.000 description 1
- 230000021523 carboxylation Effects 0.000 description 1
- 238000006473 carboxylation reaction Methods 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 208000002458 carcinoid tumor Diseases 0.000 description 1
- BLMPQMFVWMYDKT-NZTKNTHTSA-N carfilzomib Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC(C)C)C(=O)[C@]1(C)OC1)NC(=O)CN1CCOCC1)CC1=CC=CC=C1 BLMPQMFVWMYDKT-NZTKNTHTSA-N 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 239000006143 cell culture medium Substances 0.000 description 1
- 238000003783 cell cycle assay Methods 0.000 description 1
- 230000018486 cell cycle phase Effects 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 230000006037 cell lysis Effects 0.000 description 1
- 238000001516 cell proliferation assay Methods 0.000 description 1
- 238000002659 cell therapy Methods 0.000 description 1
- 238000003570 cell viability assay Methods 0.000 description 1
- 230000007248 cellular mechanism Effects 0.000 description 1
- 229920002678 cellulose Chemical class 0.000 description 1
- 239000001913 cellulose Chemical class 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229940081734 cellulose acetate phthalate Drugs 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 229910000420 cerium oxide Inorganic materials 0.000 description 1
- 201000010881 cervical cancer Diseases 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 230000009920 chelation Effects 0.000 description 1
- JQXXHWHPUNPDRT-BQVAUQFYSA-N chembl1523493 Chemical compound O([C@](C1=O)(C)O\C=C/[C@@H]([C@H]([C@@H](OC(C)=O)[C@H](C)[C@H](O)[C@H](C)[C@@H](O)[C@@H](C)/C=C\C=C(C)/C(=O)NC=2C(O)=C3C(O)=C4C)C)OC)C4=C1C3=C(O)C=2C=NN1CCN(C)CC1 JQXXHWHPUNPDRT-BQVAUQFYSA-N 0.000 description 1
- BHONFOAYRQZPKZ-LCLOTLQISA-N chembl269478 Chemical compound C([C@H](NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](N)CCCNC(N)=N)[C@@H](C)CC)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(O)=O)C1=CC=CC=C1 BHONFOAYRQZPKZ-LCLOTLQISA-N 0.000 description 1
- JROFGZPOBKIAEW-HAQNSBGRSA-N chembl3120215 Chemical compound N1C=2C(OC)=CC=CC=2C=C1C(=C1C(N)=NC=NN11)N=C1[C@H]1CC[C@H](C(O)=O)CC1 JROFGZPOBKIAEW-HAQNSBGRSA-N 0.000 description 1
- HWGQMRYQVZSGDQ-HZPDHXFCSA-N chembl3137320 Chemical compound CN1N=CN=C1[C@H]([C@H](N1)C=2C=CC(F)=CC=2)C2=NNC(=O)C3=C2C1=CC(F)=C3 HWGQMRYQVZSGDQ-HZPDHXFCSA-N 0.000 description 1
- 238000012412 chemical coupling Methods 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000000973 chemotherapeutic effect Effects 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 229940044683 chemotherapy drug Drugs 0.000 description 1
- 229960004630 chlorambucil Drugs 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- 229960004926 chlorobutanol Drugs 0.000 description 1
- AOGYCOYQMAVAFD-UHFFFAOYSA-N chlorocarbonic acid Chemical class OC(Cl)=O AOGYCOYQMAVAFD-UHFFFAOYSA-N 0.000 description 1
- 125000002603 chloroethyl group Chemical group [H]C([*])([H])C([H])([H])Cl 0.000 description 1
- 208000006990 cholangiocarcinoma Diseases 0.000 description 1
- 229910052804 chromium Inorganic materials 0.000 description 1
- 239000011651 chromium Substances 0.000 description 1
- 208000021668 chronic eosinophilic leukemia Diseases 0.000 description 1
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 description 1
- 229960000724 cidofovir Drugs 0.000 description 1
- 235000013477 citrulline Nutrition 0.000 description 1
- 229940031301 claravis Drugs 0.000 description 1
- 229960000928 clofarabine Drugs 0.000 description 1
- 229940103380 clolar Drugs 0.000 description 1
- 229910000428 cobalt oxide Inorganic materials 0.000 description 1
- IVMYJDGYRUAWML-UHFFFAOYSA-N cobalt(ii) oxide Chemical compound [Co]=O IVMYJDGYRUAWML-UHFFFAOYSA-N 0.000 description 1
- BSMCAPRUBJMWDF-KRWDZBQOSA-N cobimetinib Chemical compound C1C(O)([C@H]2NCCCC2)CN1C(=O)C1=CC=C(F)C(F)=C1NC1=CC=C(I)C=C1F BSMCAPRUBJMWDF-KRWDZBQOSA-N 0.000 description 1
- RESIMIUSNACMNW-BXRWSSRYSA-N cobimetinib fumarate Chemical compound OC(=O)\C=C\C(O)=O.C1C(O)([C@H]2NCCCC2)CN1C(=O)C1=CC=C(F)C(F)=C1NC1=CC=C(I)C=C1F.C1C(O)([C@H]2NCCCC2)CN1C(=O)C1=CC=C(F)C(F)=C1NC1=CC=C(I)C=C1F RESIMIUSNACMNW-BXRWSSRYSA-N 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 229940075614 colloidal silicon dioxide Drugs 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 238000005056 compaction Methods 0.000 description 1
- 210000002808 connective tissue Anatomy 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 229940088547 cosmegen Drugs 0.000 description 1
- 239000007822 coupling agent Substances 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- MGNCLNQXLYJVJD-UHFFFAOYSA-N cyanuric chloride Chemical compound ClC1=NC(Cl)=NC(Cl)=N1 MGNCLNQXLYJVJD-UHFFFAOYSA-N 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 229960004397 cyclophosphamide Drugs 0.000 description 1
- UHDGCWIWMRVCDJ-ZAKLUEHWSA-N cytidine Chemical class O=C1N=C(N)C=CN1[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O1 UHDGCWIWMRVCDJ-ZAKLUEHWSA-N 0.000 description 1
- 238000004163 cytometry Methods 0.000 description 1
- 239000000824 cytostatic agent Substances 0.000 description 1
- 230000001085 cytostatic effect Effects 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 210000001151 cytotoxic T lymphocyte Anatomy 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 229940059359 dacogen Drugs 0.000 description 1
- 229950006418 dactolisib Drugs 0.000 description 1
- JOGKUKXHTYWRGZ-UHFFFAOYSA-N dactolisib Chemical compound O=C1N(C)C2=CN=C3C=CC(C=4C=C5C=CC=CC5=NC=4)=CC3=C2N1C1=CC=C(C(C)(C)C#N)C=C1 JOGKUKXHTYWRGZ-UHFFFAOYSA-N 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 229960005107 darunavir Drugs 0.000 description 1
- CJBJHOAVZSMMDJ-HEXNFIEUSA-N darunavir Chemical compound C([C@@H]([C@H](O)CN(CC(C)C)S(=O)(=O)C=1C=CC(N)=CC=1)NC(=O)O[C@@H]1[C@@H]2CCO[C@@H]2OC1)C1=CC=CC=C1 CJBJHOAVZSMMDJ-HEXNFIEUSA-N 0.000 description 1
- 229960003603 decitabine Drugs 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 229960002272 degarelix Drugs 0.000 description 1
- SJFBTAPEPRWNKH-CCKFTAQKSA-N delanzomib Chemical compound CC(C)C[C@@H](B(O)O)NC(=O)[C@H]([C@@H](C)O)NC(=O)C1=CC=CC(C=2C=CC=CC=2)=N1 SJFBTAPEPRWNKH-CCKFTAQKSA-N 0.000 description 1
- 229960005319 delavirdine Drugs 0.000 description 1
- 230000001934 delay Effects 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 230000037430 deletion Effects 0.000 description 1
- 238000012217 deletion Methods 0.000 description 1
- 239000000412 dendrimer Substances 0.000 description 1
- 229920000736 dendritic polymer Polymers 0.000 description 1
- 108010017271 denileukin diftitox Proteins 0.000 description 1
- 238000010217 densitometric analysis Methods 0.000 description 1
- 229940063223 depo-provera Drugs 0.000 description 1
- 229940070968 depocyt Drugs 0.000 description 1
- 239000003599 detergent Substances 0.000 description 1
- 229960004193 dextropropoxyphene Drugs 0.000 description 1
- XLMALTXPSGQGBX-GCJKJVERSA-N dextropropoxyphene Chemical compound C([C@](OC(=O)CC)([C@H](C)CN(C)C)C=1C=CC=CC=1)C1=CC=CC=C1 XLMALTXPSGQGBX-GCJKJVERSA-N 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- NIJJYAXOARWZEE-UHFFFAOYSA-N di-n-propyl-acetic acid Natural products CCCC(C(O)=O)CCC NIJJYAXOARWZEE-UHFFFAOYSA-N 0.000 description 1
- 229940061607 dibasic sodium phosphate Drugs 0.000 description 1
- 229960002656 didanosine Drugs 0.000 description 1
- 238000001085 differential centrifugation Methods 0.000 description 1
- UGMCXQCYOVCMTB-UHFFFAOYSA-K dihydroxy(stearato)aluminium Chemical compound CCCCCCCCCCCCCCCCCC(=O)O[Al](O)O UGMCXQCYOVCMTB-UHFFFAOYSA-K 0.000 description 1
- 238000006471 dimerization reaction Methods 0.000 description 1
- FSXRLASFHBWESK-UHFFFAOYSA-N dipeptide phenylalanyl-tyrosine Natural products C=1C=C(O)C=CC=1CC(C(O)=O)NC(=O)C(N)CC1=CC=CC=C1 FSXRLASFHBWESK-UHFFFAOYSA-N 0.000 description 1
- 229940042399 direct acting antivirals protease inhibitors Drugs 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- PYLIXCKOHOHGKQ-UHFFFAOYSA-L disodium;hydrogen phosphate;heptahydrate Chemical compound O.O.O.O.O.O.O.[Na+].[Na+].OP([O-])([O-])=O PYLIXCKOHOHGKQ-UHFFFAOYSA-L 0.000 description 1
- 150000002019 disulfides Chemical class 0.000 description 1
- 229960002563 disulfiram Drugs 0.000 description 1
- AFOSIXZFDONLBT-UHFFFAOYSA-N divinyl sulfone Chemical compound C=CS(=O)(=O)C=C AFOSIXZFDONLBT-UHFFFAOYSA-N 0.000 description 1
- VSJKWCGYPAHWDS-UHFFFAOYSA-N dl-camptothecin Natural products C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-UHFFFAOYSA-N 0.000 description 1
- PMMYEEVYMWASQN-UHFFFAOYSA-N dl-hydroxyproline Natural products OC1C[NH2+]C(C([O-])=O)C1 PMMYEEVYMWASQN-UHFFFAOYSA-N 0.000 description 1
- 229960000735 docosanol Drugs 0.000 description 1
- 229940115080 doxil Drugs 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 238000002651 drug therapy Methods 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- KBQHZAAAGSGFKK-UHFFFAOYSA-N dysprosium atom Chemical compound [Dy] KBQHZAAAGSGFKK-UHFFFAOYSA-N 0.000 description 1
- 229960002224 eculizumab Drugs 0.000 description 1
- 229960003804 efavirenz Drugs 0.000 description 1
- XPOQHMRABVBWPR-ZDUSSCGKSA-N efavirenz Chemical compound C([C@]1(C2=CC(Cl)=CC=C2NC(=O)O1)C(F)(F)F)#CC1CC1 XPOQHMRABVBWPR-ZDUSSCGKSA-N 0.000 description 1
- 230000000547 effect on apoptosis Effects 0.000 description 1
- 230000000431 effect on proliferation Effects 0.000 description 1
- 229940120655 eloxatin Drugs 0.000 description 1
- 229940073038 elspar Drugs 0.000 description 1
- 229950006528 elvucitabine Drugs 0.000 description 1
- 210000002308 embryonic cell Anatomy 0.000 description 1
- 229940000733 emcyt Drugs 0.000 description 1
- 229960000366 emtricitabine Drugs 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- 208000001991 endodermal sinus tumor Diseases 0.000 description 1
- 229960000980 entecavir Drugs 0.000 description 1
- YXPVEXCTPGULBZ-WQYNNSOESA-N entecavir hydrate Chemical compound O.C1=NC=2C(=O)NC(N)=NC=2N1[C@H]1C[C@H](O)[C@@H](CO)C1=C YXPVEXCTPGULBZ-WQYNNSOESA-N 0.000 description 1
- INVTYAOGFAGBOE-UHFFFAOYSA-N entinostat Chemical compound NC1=CC=CC=C1NC(=O)C(C=C1)=CC=C1CNC(=O)OCC1=CC=CN=C1 INVTYAOGFAGBOE-UHFFFAOYSA-N 0.000 description 1
- 229950005837 entinostat Drugs 0.000 description 1
- 239000002532 enzyme inhibitor Substances 0.000 description 1
- 210000002615 epidermis Anatomy 0.000 description 1
- YJGVMLPVUAXIQN-UHFFFAOYSA-N epipodophyllotoxin Natural products COC1=C(OC)C(OC)=CC(C2C3=CC=4OCOC=4C=C3C(O)C3C2C(OC3)=O)=C1 YJGVMLPVUAXIQN-UHFFFAOYSA-N 0.000 description 1
- 210000000981 epithelium Anatomy 0.000 description 1
- HESCAJZNRMSMJG-KKQRBIROSA-N epothilone A Chemical class C/C([C@@H]1C[C@@H]2O[C@@H]2CCC[C@@H]([C@@H]([C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O1)O)C)=C\C1=CSC(C)=N1 HESCAJZNRMSMJG-KKQRBIROSA-N 0.000 description 1
- 150000003883 epothilone derivatives Chemical class 0.000 description 1
- UYAHIZSMUZPPFV-UHFFFAOYSA-N erbium Chemical compound [Er] UYAHIZSMUZPPFV-UHFFFAOYSA-N 0.000 description 1
- 229960001015 esmolol hydrochloride Drugs 0.000 description 1
- 201000004101 esophageal cancer Diseases 0.000 description 1
- 229960001842 estramustine Drugs 0.000 description 1
- FRPJXPJMRWBBIH-RBRWEJTLSA-N estramustine Chemical compound ClCCN(CCCl)C(=O)OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 FRPJXPJMRWBBIH-RBRWEJTLSA-N 0.000 description 1
- IIUMCNJTGSMNRO-VVSKJQCTSA-L estramustine sodium phosphate Chemical compound [Na+].[Na+].ClCCN(CCCl)C(=O)OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)OP([O-])([O-])=O)[C@@H]4[C@@H]3CCC2=C1 IIUMCNJTGSMNRO-VVSKJQCTSA-L 0.000 description 1
- 102000015694 estrogen receptors Human genes 0.000 description 1
- 108010038795 estrogen receptors Proteins 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 239000005038 ethylene vinyl acetate Substances 0.000 description 1
- 229960000752 etoposide phosphate Drugs 0.000 description 1
- LIQODXNTTZAGID-OCBXBXKTSA-N etoposide phosphate Chemical compound COC1=C(OP(O)(O)=O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 LIQODXNTTZAGID-OCBXBXKTSA-N 0.000 description 1
- PYGWGZALEOIKDF-UHFFFAOYSA-N etravirine Chemical compound CC1=CC(C#N)=CC(C)=C1OC1=NC(NC=2C=CC(=CC=2)C#N)=NC(N)=C1Br PYGWGZALEOIKDF-UHFFFAOYSA-N 0.000 description 1
- 229960002049 etravirine Drugs 0.000 description 1
- OGPBJKLSAFTDLK-UHFFFAOYSA-N europium atom Chemical compound [Eu] OGPBJKLSAFTDLK-UHFFFAOYSA-N 0.000 description 1
- 229940085363 evista Drugs 0.000 description 1
- 229960000255 exemestane Drugs 0.000 description 1
- 230000028023 exocytosis Effects 0.000 description 1
- OLNTVTPDXPETLC-XPWALMASSA-N ezetimibe Chemical compound N1([C@@H]([C@H](C1=O)CC[C@H](O)C=1C=CC(F)=CC=1)C=1C=CC(O)=CC=1)C1=CC=C(F)C=C1 OLNTVTPDXPETLC-XPWALMASSA-N 0.000 description 1
- 229960000815 ezetimibe Drugs 0.000 description 1
- 229960004396 famciclovir Drugs 0.000 description 1
- GGXKWVWZWMLJEH-UHFFFAOYSA-N famcyclovir Chemical compound N1=C(N)N=C2N(CCC(COC(=O)C)COC(C)=O)C=NC2=C1 GGXKWVWZWMLJEH-UHFFFAOYSA-N 0.000 description 1
- 229940043168 fareston Drugs 0.000 description 1
- 229940087476 femara Drugs 0.000 description 1
- 210000003754 fetus Anatomy 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- 238000009501 film coating Methods 0.000 description 1
- 239000007888 film coating Substances 0.000 description 1
- 229940002006 firmagon Drugs 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 229960000390 fludarabine Drugs 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- MHMNJMPURVTYEJ-UHFFFAOYSA-N fluorescein-5-isothiocyanate Chemical compound O1C(=O)C2=CC(N=C=S)=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 MHMNJMPURVTYEJ-UHFFFAOYSA-N 0.000 description 1
- 238000001917 fluorescence detection Methods 0.000 description 1
- 239000007850 fluorescent dye Substances 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 229960002949 fluorouracil Drugs 0.000 description 1
- 229960002464 fluoxetine Drugs 0.000 description 1
- MKXKFYHWDHIYRV-UHFFFAOYSA-N flutamide Chemical compound CC(C)C(=O)NC1=CC=C([N+]([O-])=O)C(C(F)(F)F)=C1 MKXKFYHWDHIYRV-UHFFFAOYSA-N 0.000 description 1
- 229940014144 folate Drugs 0.000 description 1
- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 description 1
- 239000011724 folic acid Substances 0.000 description 1
- 235000019152 folic acid Nutrition 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 229960003142 fosamprenavir Drugs 0.000 description 1
- MLBVMOWEQCZNCC-OEMFJLHTSA-N fosamprenavir Chemical compound C([C@@H]([C@H](OP(O)(O)=O)CN(CC(C)C)S(=O)(=O)C=1C=CC(N)=CC=1)NC(=O)O[C@@H]1COCC1)C1=CC=CC=C1 MLBVMOWEQCZNCC-OEMFJLHTSA-N 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 229920001002 functional polymer Polymers 0.000 description 1
- IECPWNUMDGFDKC-MZJAQBGESA-N fusidic acid Chemical class O[C@@H]([C@@H]12)C[C@H]3\C(=C(/CCC=C(C)C)C(O)=O)[C@@H](OC(C)=O)C[C@]3(C)[C@@]2(C)CC[C@@H]2[C@]1(C)CC[C@@H](O)[C@H]2C IECPWNUMDGFDKC-MZJAQBGESA-N 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 108020001507 fusion proteins Proteins 0.000 description 1
- 102000037865 fusion proteins Human genes 0.000 description 1
- UIWYJDYFSGRHKR-UHFFFAOYSA-N gadolinium atom Chemical compound [Gd] UIWYJDYFSGRHKR-UHFFFAOYSA-N 0.000 description 1
- 229930182830 galactose Natural products 0.000 description 1
- 229910052733 gallium Inorganic materials 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 206010017758 gastric cancer Diseases 0.000 description 1
- 230000030136 gastric emptying Effects 0.000 description 1
- ASKSDLRLUXEOOR-SUFRFZPQSA-N gbv-c Chemical compound C1=CC=C2C(C[C@@H](C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=3C4=CC=CC=C4NC=3)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(O)=O)NC(=O)[C@@H](N)CC(C)C)=CNC2=C1 ASKSDLRLUXEOOR-SUFRFZPQSA-N 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 description 1
- 230000009368 gene silencing by RNA Effects 0.000 description 1
- 238000001415 gene therapy Methods 0.000 description 1
- 229910052732 germanium Inorganic materials 0.000 description 1
- GNPVGFCGXDBREM-UHFFFAOYSA-N germanium atom Chemical compound [Ge] GNPVGFCGXDBREM-UHFFFAOYSA-N 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 229940084910 gliadel Drugs 0.000 description 1
- 208000005017 glioblastoma Diseases 0.000 description 1
- 229940074045 glyceryl distearate Drugs 0.000 description 1
- 229940075507 glyceryl monostearate Drugs 0.000 description 1
- 125000003827 glycol group Chemical group 0.000 description 1
- 230000013595 glycosylation Effects 0.000 description 1
- 238000006206 glycosylation reaction Methods 0.000 description 1
- JYPCXBJRLBHWME-UHFFFAOYSA-N glycyl-L-prolyl-L-arginine Natural products NCC(=O)N1CCCC1C(=O)NC(CCCN=C(N)N)C(O)=O JYPCXBJRLBHWME-UHFFFAOYSA-N 0.000 description 1
- 108010027668 glycyl-alanyl-valine Proteins 0.000 description 1
- 108010067216 glycyl-glycyl-glycine Proteins 0.000 description 1
- 108010089804 glycyl-threonine Proteins 0.000 description 1
- 108010015792 glycyllysine Proteins 0.000 description 1
- 229960002913 goserelin Drugs 0.000 description 1
- 210000003714 granulocyte Anatomy 0.000 description 1
- 229960002867 griseofulvin Drugs 0.000 description 1
- DDUHZTYCFQRHIY-RBHXEPJQSA-N griseofulvin Chemical compound COC1=CC(=O)C[C@@H](C)[C@@]11C(=O)C(C(OC)=CC(OC)=C2Cl)=C2O1 DDUHZTYCFQRHIY-RBHXEPJQSA-N 0.000 description 1
- SCMLRESZJCKCTC-KMYQRJGFSA-N gtpl8173 Chemical compound C12=CC=C(CSCC)C=C2C2=C(CNC3=O)C3=C3C4=CC(CSCC)=CC=C4N4C3=C2N1[C@]1(C)[C@@](O)(C(=O)OC)C[C@H]4O1 SCMLRESZJCKCTC-KMYQRJGFSA-N 0.000 description 1
- 229940029575 guanosine Drugs 0.000 description 1
- 229910052735 hafnium Inorganic materials 0.000 description 1
- VBJZVLUMGGDVMO-UHFFFAOYSA-N hafnium atom Chemical compound [Hf] VBJZVLUMGGDVMO-UHFFFAOYSA-N 0.000 description 1
- 201000009277 hairy cell leukemia Diseases 0.000 description 1
- 229940083461 halotestin Drugs 0.000 description 1
- 210000003128 head Anatomy 0.000 description 1
- 210000003566 hemangioblast Anatomy 0.000 description 1
- 201000002222 hemangioblastoma Diseases 0.000 description 1
- 201000005787 hematologic cancer Diseases 0.000 description 1
- 208000024200 hematopoietic and lymphoid system neoplasm Diseases 0.000 description 1
- 230000002008 hemorrhagic effect Effects 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 1
- 235000019514 herring Nutrition 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 229940003183 hexalen Drugs 0.000 description 1
- 210000003630 histaminocyte Anatomy 0.000 description 1
- 150000002410 histidine derivatives Chemical class 0.000 description 1
- 108010036413 histidylglycine Proteins 0.000 description 1
- 108010092114 histidylphenylalanine Proteins 0.000 description 1
- 108010085325 histidylproline Proteins 0.000 description 1
- 239000002835 hiv fusion inhibitor Substances 0.000 description 1
- KJZYNXUDTRRSPN-UHFFFAOYSA-N holmium atom Chemical compound [Ho] KJZYNXUDTRRSPN-UHFFFAOYSA-N 0.000 description 1
- 230000013632 homeostatic process Effects 0.000 description 1
- 235000001050 hortel pimenta Nutrition 0.000 description 1
- 210000005260 human cell Anatomy 0.000 description 1
- 208000033519 human immunodeficiency virus infectious disease Diseases 0.000 description 1
- 239000003906 humectant Substances 0.000 description 1
- 229920002674 hyaluronan Polymers 0.000 description 1
- 229960003160 hyaluronic acid Drugs 0.000 description 1
- 229940088013 hycamtin Drugs 0.000 description 1
- 150000007857 hydrazones Chemical class 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 1
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 1
- 229960002591 hydroxyproline Drugs 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 229920000639 hydroxypropylmethylcellulose acetate succinate Polymers 0.000 description 1
- 230000000148 hypercalcaemia Effects 0.000 description 1
- 208000030915 hypercalcemia disease Diseases 0.000 description 1
- 230000001157 hypermorphic effect Effects 0.000 description 1
- 229940090411 ifex Drugs 0.000 description 1
- 229960001101 ifosfamide Drugs 0.000 description 1
- KTUFNOKKBVMGRW-UHFFFAOYSA-N imatinib Chemical compound C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 KTUFNOKKBVMGRW-UHFFFAOYSA-N 0.000 description 1
- 210000002865 immune cell Anatomy 0.000 description 1
- 230000005847 immunogenicity Effects 0.000 description 1
- 229940072221 immunoglobulins Drugs 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 201000004933 in situ carcinoma Diseases 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 229960001936 indinavir Drugs 0.000 description 1
- CBVCZFGXHXORBI-PXQQMZJSSA-N indinavir Chemical compound C([C@H](N(CC1)C[C@@H](O)C[C@@H](CC=2C=CC=CC=2)C(=O)N[C@H]2C3=CC=CC=C3C[C@H]2O)C(=O)NC(C)(C)C)N1CC1=CC=CN=C1 CBVCZFGXHXORBI-PXQQMZJSSA-N 0.000 description 1
- 229910052738 indium Inorganic materials 0.000 description 1
- APFVFJFRJDLVQX-UHFFFAOYSA-N indium atom Chemical compound [In] APFVFJFRJDLVQX-UHFFFAOYSA-N 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 229950002133 iniparib Drugs 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 229940124524 integrase inhibitor Drugs 0.000 description 1
- 239000002850 integrase inhibitor Substances 0.000 description 1
- 230000002452 interceptive effect Effects 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 238000000185 intracerebroventricular administration Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 230000002601 intratumoral effect Effects 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 229940065638 intron a Drugs 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 229910052741 iridium Inorganic materials 0.000 description 1
- GKOZUEZYRPOHIO-UHFFFAOYSA-N iridium atom Chemical compound [Ir] GKOZUEZYRPOHIO-UHFFFAOYSA-N 0.000 description 1
- 229960004768 irinotecan Drugs 0.000 description 1
- 239000013038 irreversible inhibitor Substances 0.000 description 1
- 108010044374 isoleucyl-tyrosine Proteins 0.000 description 1
- 108010078274 isoleucylvaline Proteins 0.000 description 1
- QRXWMOHMRWLFEY-UHFFFAOYSA-N isoniazide Chemical compound NNC(=O)C1=CC=NC=C1 QRXWMOHMRWLFEY-UHFFFAOYSA-N 0.000 description 1
- FABUFPQFXZVHFB-PVYNADRNSA-N ixabepilone Chemical compound C/C([C@@H]1C[C@@H]2O[C@]2(C)CCC[C@@H]([C@@H]([C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)N1)O)C)=C\C1=CSC(C)=N1 FABUFPQFXZVHFB-PVYNADRNSA-N 0.000 description 1
- MXAYKZJJDUDWDS-LBPRGKRZSA-N ixazomib Chemical compound CC(C)C[C@@H](B(O)O)NC(=O)CNC(=O)C1=CC(Cl)=CC=C1Cl MXAYKZJJDUDWDS-LBPRGKRZSA-N 0.000 description 1
- MBOMYENWWXQSNW-AWEZNQCLSA-N ixazomib citrate Chemical compound N([C@@H](CC(C)C)B1OC(CC(O)=O)(CC(O)=O)C(=O)O1)C(=O)CNC(=O)C1=CC(Cl)=CC=C1Cl MBOMYENWWXQSNW-AWEZNQCLSA-N 0.000 description 1
- 229940111707 ixempra Drugs 0.000 description 1
- WXNQMDPKECZMAO-ASGAITCASA-N kai9803 Chemical compound C([C@@H](C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CSSC[C@H](N)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C1=CC=C(O)C=C1 WXNQMDPKECZMAO-ASGAITCASA-N 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 230000002147 killing effect Effects 0.000 description 1
- WZNJWVWKTVETCG-UHFFFAOYSA-N kojic acid Natural products OC(=O)C(N)CN1C=CC(=O)C(O)=C1 WZNJWVWKTVETCG-UHFFFAOYSA-N 0.000 description 1
- 229960001627 lamivudine Drugs 0.000 description 1
- JTEGQNOMFQHVDC-NKWVEPMBSA-N lamivudine Chemical compound O=C1N=C(N)C=CN1[C@H]1O[C@@H](CO)SC1 JTEGQNOMFQHVDC-NKWVEPMBSA-N 0.000 description 1
- 229910052747 lanthanoid Inorganic materials 0.000 description 1
- 150000002602 lanthanoids Chemical class 0.000 description 1
- 229910052746 lanthanum Inorganic materials 0.000 description 1
- FZLIPJUXYLNCLC-UHFFFAOYSA-N lanthanum atom Chemical compound [La] FZLIPJUXYLNCLC-UHFFFAOYSA-N 0.000 description 1
- 208000003849 large cell carcinoma Diseases 0.000 description 1
- 239000004816 latex Substances 0.000 description 1
- 229920000126 latex Polymers 0.000 description 1
- DDVBPZROPPMBLW-ZJBINBEQSA-N latrunculin a Chemical compound C([C@H]1[C@@]2(O)C[C@H]3C[C@H](O2)CC[C@@H](/C=C\C=C/CC\C(C)=C/C(=O)O3)C)SC(=O)N1 DDVBPZROPPMBLW-ZJBINBEQSA-N 0.000 description 1
- DDVBPZROPPMBLW-UHFFFAOYSA-N latrunculin-A Natural products O1C(=O)C=C(C)CCC=CC=CC(C)CCC(O2)CC1CC2(O)C1CSC(=O)N1 DDVBPZROPPMBLW-UHFFFAOYSA-N 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 229960004942 lenalidomide Drugs 0.000 description 1
- GOTYRUGSSMKFNF-UHFFFAOYSA-N lenalidomide Chemical compound C1C=2C(N)=CC=CC=2C(=O)N1C1CCC(=O)NC1=O GOTYRUGSSMKFNF-UHFFFAOYSA-N 0.000 description 1
- 206010024217 lentigo Diseases 0.000 description 1
- 229960003881 letrozole Drugs 0.000 description 1
- 108010034529 leucyl-lysine Proteins 0.000 description 1
- 229940063725 leukeran Drugs 0.000 description 1
- 210000000265 leukocyte Anatomy 0.000 description 1
- 229960001614 levamisole Drugs 0.000 description 1
- 206010024627 liposarcoma Diseases 0.000 description 1
- 239000008297 liquid dosage form Substances 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000037841 lung tumor Diseases 0.000 description 1
- 108010078259 luprolide acetate gel depot Proteins 0.000 description 1
- OHSVLFRHMCKCQY-UHFFFAOYSA-N lutetium atom Chemical compound [Lu] OHSVLFRHMCKCQY-UHFFFAOYSA-N 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 201000010953 lymphoepithelioma-like carcinoma Diseases 0.000 description 1
- 239000008176 lyophilized powder Substances 0.000 description 1
- 239000006166 lysate Substances 0.000 description 1
- 125000003588 lysine group Chemical group [H]N([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 108010043322 lysyl-tryptophyl-alpha-lysine Proteins 0.000 description 1
- 108010009298 lysylglutamic acid Proteins 0.000 description 1
- 108010064235 lysylglycine Proteins 0.000 description 1
- 229920001427 mPEG Polymers 0.000 description 1
- 229940124302 mTOR inhibitor Drugs 0.000 description 1
- 201000000564 macroglobulinemia Diseases 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 208000025854 malignant tumor of adrenal cortex Diseases 0.000 description 1
- 239000003628 mammalian target of rapamycin inhibitor Substances 0.000 description 1
- 210000005075 mammary gland Anatomy 0.000 description 1
- WPBNNNQJVZRUHP-UHFFFAOYSA-L manganese(2+);methyl n-[[2-(methoxycarbonylcarbamothioylamino)phenyl]carbamothioyl]carbamate;n-[2-(sulfidocarbothioylamino)ethyl]carbamodithioate Chemical compound [Mn+2].[S-]C(=S)NCCNC([S-])=S.COC(=O)NC(=S)NC1=CC=CC=C1NC(=S)NC(=O)OC WPBNNNQJVZRUHP-UHFFFAOYSA-L 0.000 description 1
- GSNHKUDZZFZSJB-QYOOZWMWSA-N maraviroc Chemical compound CC(C)C1=NN=C(C)N1[C@@H]1C[C@H](N2CC[C@H](NC(=O)C3CCC(F)(F)CC3)C=3C=CC=CC=3)CC[C@H]2C1 GSNHKUDZZFZSJB-QYOOZWMWSA-N 0.000 description 1
- 229960004710 maraviroc Drugs 0.000 description 1
- 229950002736 marizomib Drugs 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 208000000516 mast-cell leukemia Diseases 0.000 description 1
- 230000035800 maturation Effects 0.000 description 1
- 229950008001 matuzumab Drugs 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 229960004616 medroxyprogesterone Drugs 0.000 description 1
- 208000023356 medullary thyroid gland carcinoma Diseases 0.000 description 1
- 229940090004 megace Drugs 0.000 description 1
- RQZAXGRLVPAYTJ-GQFGMJRRSA-N megestrol acetate Chemical compound C1=C(C)C2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(C)=O)(OC(=O)C)[C@@]1(C)CC2 RQZAXGRLVPAYTJ-GQFGMJRRSA-N 0.000 description 1
- 229960001924 melphalan Drugs 0.000 description 1
- GLVAUDGFNGKCSF-UHFFFAOYSA-N mercaptopurine Chemical compound S=C1NC=NC2=C1NC=N2 GLVAUDGFNGKCSF-UHFFFAOYSA-N 0.000 description 1
- 229960004635 mesna Drugs 0.000 description 1
- 229940101533 mesnex Drugs 0.000 description 1
- 229920003145 methacrylic acid copolymer Polymers 0.000 description 1
- 229960004452 methionine Drugs 0.000 description 1
- 108010034507 methionyltryptophan Proteins 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- VDOCQQKGPJENHJ-UHFFFAOYSA-N methyl n-[4-[4-morpholin-4-yl-1-[1-(pyridin-3-ylmethyl)piperidin-4-yl]pyrazolo[3,4-d]pyrimidin-6-yl]phenyl]carbamate Chemical compound C1=CC(NC(=O)OC)=CC=C1C1=NC(N2CCOCC2)=C(C=NN2C3CCN(CC=4C=NC=CC=4)CC3)C2=N1 VDOCQQKGPJENHJ-UHFFFAOYSA-N 0.000 description 1
- STZCRXQWRGQSJD-GEEYTBSJSA-M methyl orange Chemical compound [Na+].C1=CC(N(C)C)=CC=C1\N=N\C1=CC=C(S([O-])(=O)=O)C=C1 STZCRXQWRGQSJD-GEEYTBSJSA-M 0.000 description 1
- 229940012189 methyl orange Drugs 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 229960001047 methyl salicylate Drugs 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 229960002216 methylparaben Drugs 0.000 description 1
- 239000002679 microRNA Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- BMGQWWVMWDBQGC-IIFHNQTCSA-N midostaurin Chemical compound CN([C@H]1[C@H]([C@]2(C)O[C@@H](N3C4=CC=CC=C4C4=C5C(=O)NCC5=C5C6=CC=CC=C6N2C5=C43)C1)OC)C(=O)C1=CC=CC=C1 BMGQWWVMWDBQGC-IIFHNQTCSA-N 0.000 description 1
- 229950010895 midostaurin Drugs 0.000 description 1
- 229960003775 miltefosine Drugs 0.000 description 1
- PQLXHQMOHUQAKB-UHFFFAOYSA-N miltefosine Chemical compound CCCCCCCCCCCCCCCCOP([O-])(=O)OCC[N+](C)(C)C PQLXHQMOHUQAKB-UHFFFAOYSA-N 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 229960001156 mitoxantrone Drugs 0.000 description 1
- 229960004938 molindone Drugs 0.000 description 1
- ZDZOTLJHXYCWBA-BSEPLHNVSA-N molport-006-823-826 Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-BSEPLHNVSA-N 0.000 description 1
- 229910052750 molybdenum Inorganic materials 0.000 description 1
- 239000011733 molybdenum Substances 0.000 description 1
- 229940045641 monobasic sodium phosphate Drugs 0.000 description 1
- 201000006894 monocytic leukemia Diseases 0.000 description 1
- 230000003427 mucosecretory effect Effects 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 201000005987 myeloid sarcoma Diseases 0.000 description 1
- 229940090009 myleran Drugs 0.000 description 1
- 208000031225 myocardial ischemia Diseases 0.000 description 1
- 208000009091 myxoma Diseases 0.000 description 1
- 208000001611 myxosarcoma Diseases 0.000 description 1
- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 1
- AXTAPYRUEKNRBA-JTQLQIEISA-N n-[(2s)-1-amino-3-(3,4-difluorophenyl)propan-2-yl]-5-chloro-4-(4-chloro-2-methylpyrazol-3-yl)furan-2-carboxamide Chemical compound CN1N=CC(Cl)=C1C1=C(Cl)OC(C(=O)N[C@H](CN)CC=2C=C(F)C(F)=CC=2)=C1 AXTAPYRUEKNRBA-JTQLQIEISA-N 0.000 description 1
- SWZXEVABPLUDIO-WSZYKNRRSA-N n-[(2s)-3-methoxy-1-[[(2s)-3-methoxy-1-[[(2s)-1-[(2r)-2-methyloxiran-2-yl]-1-oxo-3-phenylpropan-2-yl]amino]-1-oxopropan-2-yl]amino]-1-oxopropan-2-yl]-2-methyl-1,3-thiazole-5-carboxamide Chemical compound N([C@@H](COC)C(=O)N[C@@H](COC)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)[C@]1(C)OC1)C(=O)C1=CN=C(C)S1 SWZXEVABPLUDIO-WSZYKNRRSA-N 0.000 description 1
- PCZTWTWJVSEJSX-UHFFFAOYSA-N n-benzyl-5-nitrofuran-2-carboxamide Chemical compound O1C([N+](=O)[O-])=CC=C1C(=O)NCC1=CC=CC=C1 PCZTWTWJVSEJSX-UHFFFAOYSA-N 0.000 description 1
- 239000002088 nanocapsule Substances 0.000 description 1
- 239000007908 nanoemulsion Substances 0.000 description 1
- 239000002121 nanofiber Substances 0.000 description 1
- 239000002073 nanorod Substances 0.000 description 1
- 239000002077 nanosphere Substances 0.000 description 1
- 239000002071 nanotube Substances 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- PLPRGLOFPNJOTN-UHFFFAOYSA-N narcotine Natural products COc1ccc2C(OC(=O)c2c1OC)C3Cc4c(CN3C)cc5OCOc5c4OC PLPRGLOFPNJOTN-UHFFFAOYSA-N 0.000 description 1
- 239000006218 nasal suppository Substances 0.000 description 1
- 208000014761 nasopharyngeal type undifferentiated carcinoma Diseases 0.000 description 1
- 210000000822 natural killer cell Anatomy 0.000 description 1
- 229940086322 navelbine Drugs 0.000 description 1
- 239000006199 nebulizer Substances 0.000 description 1
- 210000003739 neck Anatomy 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- 229960000801 nelarabine Drugs 0.000 description 1
- IXOXBSCIXZEQEQ-UHTZMRCNSA-N nelarabine Chemical compound C1=NC=2C(OC)=NC(N)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1O IXOXBSCIXZEQEQ-UHTZMRCNSA-N 0.000 description 1
- 229960000884 nelfinavir Drugs 0.000 description 1
- QAGYKUNXZHXKMR-HKWSIXNMSA-N nelfinavir Chemical compound CC1=C(O)C=CC=C1C(=O)N[C@H]([C@H](O)CN1[C@@H](C[C@@H]2CCCC[C@@H]2C1)C(=O)NC(C)(C)C)CSC1=CC=CC=C1 QAGYKUNXZHXKMR-HKWSIXNMSA-N 0.000 description 1
- QEFYFXOXNSNQGX-UHFFFAOYSA-N neodymium atom Chemical compound [Nd] QEFYFXOXNSNQGX-UHFFFAOYSA-N 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 210000000440 neutrophil Anatomy 0.000 description 1
- 229960000689 nevirapine Drugs 0.000 description 1
- 229940099637 nilandron Drugs 0.000 description 1
- 229960001346 nilotinib Drugs 0.000 description 1
- 229960002653 nilutamide Drugs 0.000 description 1
- 229910052758 niobium Inorganic materials 0.000 description 1
- 239000010955 niobium Substances 0.000 description 1
- GUCVJGMIXFAOAE-UHFFFAOYSA-N niobium atom Chemical compound [Nb] GUCVJGMIXFAOAE-UHFFFAOYSA-N 0.000 description 1
- 229940109551 nipent Drugs 0.000 description 1
- PCHKPVIQAHNQLW-CQSZACIVSA-N niraparib Chemical compound N1=C2C(C(=O)N)=CC=CC2=CN1C(C=C1)=CC=C1[C@@H]1CCCNC1 PCHKPVIQAHNQLW-CQSZACIVSA-N 0.000 description 1
- 201000000032 nodular malignant melanoma Diseases 0.000 description 1
- 229940085033 nolvadex Drugs 0.000 description 1
- 208000029809 non-keratinizing sinonasal squamous cell carcinoma Diseases 0.000 description 1
- 231100000956 nontoxicity Toxicity 0.000 description 1
- 239000000346 nonvolatile oil Substances 0.000 description 1
- 229960004708 noscapine Drugs 0.000 description 1
- FAQDUNYVKQKNLD-UHFFFAOYSA-N olaparib Chemical compound FC1=CC=C(CC2=C3[CH]C=CC=C3C(=O)N=N2)C=C1C(=O)N(CC1)CCN1C(=O)C1CC1 FAQDUNYVKQKNLD-UHFFFAOYSA-N 0.000 description 1
- 229960000572 olaparib Drugs 0.000 description 1
- JLPDBLFIVFSOCC-XYXFTTADSA-N oleandrin Chemical compound O1[C@@H](C)[C@H](O)[C@@H](OC)C[C@@H]1O[C@@H]1C[C@@H](CC[C@H]2[C@]3(C[C@@H]([C@@H]([C@@]3(C)CC[C@H]32)C=2COC(=O)C=2)OC(C)=O)O)[C@]3(C)CC1 JLPDBLFIVFSOCC-XYXFTTADSA-N 0.000 description 1
- 231100000590 oncogenic Toxicity 0.000 description 1
- 230000002246 oncogenic effect Effects 0.000 description 1
- 229940100027 ontak Drugs 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 125000002524 organometallic group Chemical group 0.000 description 1
- 229960003104 ornithine Drugs 0.000 description 1
- 150000002905 orthoesters Chemical class 0.000 description 1
- 229960003752 oseltamivir Drugs 0.000 description 1
- NENPYTRHICXVCS-YNEHKIRRSA-N oseltamivir acid Chemical compound CCC(CC)O[C@@H]1C=C(C(O)=O)C[C@H](N)[C@H]1NC(C)=O NENPYTRHICXVCS-YNEHKIRRSA-N 0.000 description 1
- 229910052762 osmium Inorganic materials 0.000 description 1
- SYQBFIAQOQZEGI-UHFFFAOYSA-N osmium atom Chemical compound [Os] SYQBFIAQOQZEGI-UHFFFAOYSA-N 0.000 description 1
- 230000002611 ovarian Effects 0.000 description 1
- 229960001756 oxaliplatin Drugs 0.000 description 1
- DWAFYCQODLXJNR-BNTLRKBRSA-L oxaliplatin Chemical compound O1C(=O)C(=O)O[Pt]11N[C@@H]2CCCC[C@H]2N1 DWAFYCQODLXJNR-BNTLRKBRSA-L 0.000 description 1
- 150000002924 oxiranes Chemical group 0.000 description 1
- BMMGVYCKOGBVEV-UHFFFAOYSA-N oxo(oxoceriooxy)cerium Chemical compound [Ce]=O.O=[Ce]=O BMMGVYCKOGBVEV-UHFFFAOYSA-N 0.000 description 1
- IWVCMVBTMGNXQD-PXOLEDIWSA-N oxytetracycline Chemical compound C1=CC=C2[C@](O)(C)[C@H]3[C@H](O)[C@H]4[C@H](N(C)C)C(O)=C(C(N)=O)C(=O)[C@@]4(O)C(O)=C3C(=O)C2=C1O IWVCMVBTMGNXQD-PXOLEDIWSA-N 0.000 description 1
- 229960000625 oxytetracycline Drugs 0.000 description 1
- 235000019366 oxytetracycline Nutrition 0.000 description 1
- 239000003002 pH adjusting agent Substances 0.000 description 1
- 210000002741 palatine tonsil Anatomy 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 201000010198 papillary carcinoma Diseases 0.000 description 1
- 230000005298 paramagnetic effect Effects 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 229960000639 pazopanib Drugs 0.000 description 1
- WVUNYSQLFKLYNI-AATRIKPKSA-N pelitinib Chemical compound C=12C=C(NC(=O)\C=C\CN(C)C)C(OCC)=CC2=NC=C(C#N)C=1NC1=CC=C(F)C(Cl)=C1 WVUNYSQLFKLYNI-AATRIKPKSA-N 0.000 description 1
- 229960005079 pemetrexed Drugs 0.000 description 1
- WBXPDJSOTKVWSJ-ZDUSSCGKSA-N pemetrexed Chemical compound C=1NC=2NC(N)=NC(=O)C=2C=1CCC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 WBXPDJSOTKVWSJ-ZDUSSCGKSA-N 0.000 description 1
- NYDXNILOWQXUOF-GXKRWWSZSA-L pemetrexed disodium Chemical compound [Na+].[Na+].C=1NC=2NC(N)=NC(=O)C=2C=1CCC1=CC=C(C(=O)N[C@@H](CCC([O-])=O)C([O-])=O)C=C1 NYDXNILOWQXUOF-GXKRWWSZSA-L 0.000 description 1
- 229960001179 penciclovir Drugs 0.000 description 1
- MCYTYTUNNNZWOK-LCLOTLQISA-N penetratin Chemical compound C([C@H](NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](N)CCCNC(N)=N)[C@@H](C)CC)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(N)=O)C1=CC=CC=C1 MCYTYTUNNNZWOK-LCLOTLQISA-N 0.000 description 1
- 108010043655 penetratin Proteins 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 229960001639 penicillamine Drugs 0.000 description 1
- 229960002340 pentostatin Drugs 0.000 description 1
- 230000007030 peptide scission Effects 0.000 description 1
- 125000001151 peptidyl group Chemical group 0.000 description 1
- 229960001084 peramivir Drugs 0.000 description 1
- XRQDFNLINLXZLB-CKIKVBCHSA-N peramivir Chemical compound CCC(CC)[C@H](NC(C)=O)[C@@H]1[C@H](O)[C@@H](C(O)=O)C[C@H]1NC(N)=N XRQDFNLINLXZLB-CKIKVBCHSA-N 0.000 description 1
- KHIWWQKSHDUIBK-UHFFFAOYSA-N periodic acid Chemical compound OI(=O)(=O)=O KHIWWQKSHDUIBK-UHFFFAOYSA-N 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 229960003742 phenol Drugs 0.000 description 1
- 108010018625 phenylalanylarginine Proteins 0.000 description 1
- 108010051242 phenylalanylserine Proteins 0.000 description 1
- 150000008104 phosphatidylethanolamines Chemical class 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 229940109328 photofrin Drugs 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 229960002292 piperacillin Drugs 0.000 description 1
- WCMIIGXFCMNQDS-IDYPWDAWSA-M piperacillin sodium Chemical compound [Na+].O=C1C(=O)N(CC)CCN1C(=O)N[C@H](C=1C=CC=CC=1)C(=O)N[C@@H]1C(=O)N2[C@@H](C([O-])=O)C(C)(C)S[C@@H]21 WCMIIGXFCMNQDS-IDYPWDAWSA-M 0.000 description 1
- 208000031223 plasma cell leukemia Diseases 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 229940012957 plasmin Drugs 0.000 description 1
- 210000004180 plasmocyte Anatomy 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229940063179 platinol Drugs 0.000 description 1
- 229960001237 podophyllotoxin Drugs 0.000 description 1
- YJGVMLPVUAXIQN-XVVDYKMHSA-N podophyllotoxin Chemical compound COC1=C(OC)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@H](O)[C@@H]3[C@@H]2C(OC3)=O)=C1 YJGVMLPVUAXIQN-XVVDYKMHSA-N 0.000 description 1
- YVCVYCSAAZQOJI-UHFFFAOYSA-N podophyllotoxin Natural products COC1=C(O)C(OC)=CC(C2C3=CC=4OCOC=4C=C3C(O)C3C2C(OC3)=O)=C1 YVCVYCSAAZQOJI-UHFFFAOYSA-N 0.000 description 1
- 229910052699 polonium Inorganic materials 0.000 description 1
- HZEBHPIOVYHPMT-UHFFFAOYSA-N polonium atom Chemical compound [Po] HZEBHPIOVYHPMT-UHFFFAOYSA-N 0.000 description 1
- 229920000191 poly(N-vinyl pyrrolidone) Polymers 0.000 description 1
- 229920001308 poly(aminoacid) Polymers 0.000 description 1
- 229920001200 poly(ethylene-vinyl acetate) Polymers 0.000 description 1
- 229920000747 poly(lactic acid) Polymers 0.000 description 1
- 229920001606 poly(lactic acid-co-glycolic acid) Polymers 0.000 description 1
- 229920001583 poly(oxyethylated polyols) Polymers 0.000 description 1
- 229920002627 poly(phosphazenes) Polymers 0.000 description 1
- 230000008488 polyadenylation Effects 0.000 description 1
- 229920001610 polycaprolactone Polymers 0.000 description 1
- 239000004632 polycaprolactone Substances 0.000 description 1
- 229920000728 polyester Polymers 0.000 description 1
- 239000008389 polyethoxylated castor oil Substances 0.000 description 1
- 239000004633 polyglycolic acid Substances 0.000 description 1
- 239000004626 polylactic acid Substances 0.000 description 1
- 229920000656 polylysine Polymers 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 239000003910 polypeptide antibiotic agent Substances 0.000 description 1
- 229920001451 polypropylene glycol Polymers 0.000 description 1
- 229920002635 polyurethane Polymers 0.000 description 1
- 239000004814 polyurethane Substances 0.000 description 1
- 229940100467 polyvinyl acetate phthalate Drugs 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 210000003240 portal vein Anatomy 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- OGSBUKJUDHAQEA-WMCAAGNKSA-N pralatrexate Chemical compound C1=NC2=NC(N)=NC(N)=C2N=C1CC(CC#C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OGSBUKJUDHAQEA-WMCAAGNKSA-N 0.000 description 1
- PUDIUYLPXJFUGB-UHFFFAOYSA-N praseodymium atom Chemical compound [Pr] PUDIUYLPXJFUGB-UHFFFAOYSA-N 0.000 description 1
- VWBQYTRBTXKKOG-IYNICTALSA-M pravastatin sodium Chemical compound [Na+].C1=C[C@H](C)[C@H](CC[C@@H](O)C[C@@H](O)CC([O-])=O)[C@H]2[C@@H](OC(=O)[C@@H](C)CC)C[C@H](O)C=C21 VWBQYTRBTXKKOG-IYNICTALSA-M 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 208000030266 primary brain neoplasm Diseases 0.000 description 1
- CPTBDICYNRMXFX-UHFFFAOYSA-N procarbazine Chemical compound CNNCC1=CC=C(C(=O)NC(C)C)C=C1 CPTBDICYNRMXFX-UHFFFAOYSA-N 0.000 description 1
- 229960000624 procarbazine Drugs 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 229960003387 progesterone Drugs 0.000 description 1
- 239000000186 progesterone Substances 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 229940087463 proleukin Drugs 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 125000001500 prolyl group Chemical group [H]N1C([H])(C(=O)[*])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 108010004914 prolylarginine Proteins 0.000 description 1
- 108010070643 prolylglutamic acid Proteins 0.000 description 1
- 108010090894 prolylleucine Proteins 0.000 description 1
- 108010053725 prolylvaline Proteins 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- XJMOSONTPMZWPB-UHFFFAOYSA-M propidium iodide Chemical compound [I-].[I-].C12=CC(N)=CC=C2C2=CC=C(N)C=C2[N+](CCC[N+](C)(CC)CC)=C1C1=CC=CC=C1 XJMOSONTPMZWPB-UHFFFAOYSA-M 0.000 description 1
- 150000005599 propionic acid derivatives Chemical class 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 230000004853 protein function Effects 0.000 description 1
- 230000006916 protein interaction Effects 0.000 description 1
- 230000009145 protein modification Effects 0.000 description 1
- 230000002797 proteolythic effect Effects 0.000 description 1
- 229940063222 provera Drugs 0.000 description 1
- 229940117820 purinethol Drugs 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 239000002096 quantum dot Substances 0.000 description 1
- 229950001626 quizartinib Drugs 0.000 description 1
- 229960004622 raloxifene Drugs 0.000 description 1
- 229960004742 raltegravir Drugs 0.000 description 1
- CZFFBEXEKNGXKS-UHFFFAOYSA-N raltegravir Chemical compound O1C(C)=NN=C1C(=O)NC(C)(C)C1=NC(C(=O)NCC=2C=CC(F)=CC=2)=C(O)C(=O)N1C CZFFBEXEKNGXKS-UHFFFAOYSA-N 0.000 description 1
- 229920005604 random copolymer Polymers 0.000 description 1
- 229960003876 ranibizumab Drugs 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 229940061374 relenza Drugs 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 150000004492 retinoid derivatives Chemical class 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 201000009410 rhabdomyosarcoma Diseases 0.000 description 1
- 229910052702 rhenium Inorganic materials 0.000 description 1
- WUAPFZMCVAUBPE-UHFFFAOYSA-N rhenium atom Chemical compound [Re] WUAPFZMCVAUBPE-UHFFFAOYSA-N 0.000 description 1
- 229940061969 rheumatrex Drugs 0.000 description 1
- 229960000329 ribavirin Drugs 0.000 description 1
- HZCAHMRRMINHDJ-DBRKOABJSA-N ribavirin Natural products O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1N=CN=C1 HZCAHMRRMINHDJ-DBRKOABJSA-N 0.000 description 1
- 229960001225 rifampicin Drugs 0.000 description 1
- 229960000311 ritonavir Drugs 0.000 description 1
- NCDNCNXCDXHOMX-XGKFQTDJSA-N ritonavir Chemical compound N([C@@H](C(C)C)C(=O)N[C@H](C[C@H](O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1SC=NC=1)CC=1C=CC=CC=1)C(=O)N(C)CC1=CSC(C(C)C)=N1 NCDNCNXCDXHOMX-XGKFQTDJSA-N 0.000 description 1
- OHRURASPPZQGQM-GCCNXGTGSA-N romidepsin Chemical compound O1C(=O)[C@H](C(C)C)NC(=O)C(=C/C)/NC(=O)[C@H]2CSSCC\C=C\[C@@H]1CC(=O)N[C@H](C(C)C)C(=O)N2 OHRURASPPZQGQM-GCCNXGTGSA-N 0.000 description 1
- 229960003452 romidepsin Drugs 0.000 description 1
- 108010091666 romidepsin Proteins 0.000 description 1
- OHRURASPPZQGQM-UHFFFAOYSA-N romidepsin Natural products O1C(=O)C(C(C)C)NC(=O)C(=CC)NC(=O)C2CSSCCC=CC1CC(=O)NC(C(C)C)C(=O)N2 OHRURASPPZQGQM-UHFFFAOYSA-N 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- NGWSFRIPKNWYAO-SHTIJGAHSA-N salinosporamide A Chemical compound C([C@@H]1[C@H](O)[C@]23C(=O)O[C@]2([C@H](C(=O)N3)CCCl)C)CCC=C1 NGWSFRIPKNWYAO-SHTIJGAHSA-N 0.000 description 1
- 201000007416 salivary gland adenoid cystic carcinoma Diseases 0.000 description 1
- 229950009216 sapanisertib Drugs 0.000 description 1
- 229960001852 saquinavir Drugs 0.000 description 1
- QWAXKHKRTORLEM-UGJKXSETSA-N saquinavir Chemical compound C([C@@H]([C@H](O)CN1C[C@H]2CCCC[C@H]2C[C@H]1C(=O)NC(C)(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)C=1N=C2C=CC=CC2=CC=1)C1=CC=CC=C1 QWAXKHKRTORLEM-UGJKXSETSA-N 0.000 description 1
- 229950009919 saracatinib Drugs 0.000 description 1
- OUKYUETWWIPKQR-UHFFFAOYSA-N saracatinib Chemical compound C1CN(C)CCN1CCOC1=CC(OC2CCOCC2)=C(C(NC=2C(=CC=C3OCOC3=2)Cl)=NC=N2)C2=C1 OUKYUETWWIPKQR-UHFFFAOYSA-N 0.000 description 1
- 201000000306 sarcoidosis Diseases 0.000 description 1
- 208000014212 sarcomatoid carcinoma Diseases 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229910052706 scandium Inorganic materials 0.000 description 1
- SIXSYDAISGFNSX-UHFFFAOYSA-N scandium atom Chemical compound [Sc] SIXSYDAISGFNSX-UHFFFAOYSA-N 0.000 description 1
- 150000003335 secondary amines Chemical group 0.000 description 1
- 230000009962 secretion pathway Effects 0.000 description 1
- 229950000055 seliciclib Drugs 0.000 description 1
- 229950010746 selumetinib Drugs 0.000 description 1
- 239000004054 semiconductor nanocrystal Substances 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 235000020183 skimmed milk Nutrition 0.000 description 1
- 201000000849 skin cancer Diseases 0.000 description 1
- 201000008261 skin carcinoma Diseases 0.000 description 1
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 1
- 229910000342 sodium bisulfate Inorganic materials 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- BBMHARZCALWXSL-UHFFFAOYSA-M sodium dihydrogenphosphate monohydrate Chemical compound O.[Na+].OP(O)([O-])=O BBMHARZCALWXSL-UHFFFAOYSA-M 0.000 description 1
- 239000012064 sodium phosphate buffer Substances 0.000 description 1
- 229940074404 sodium succinate Drugs 0.000 description 1
- ZDQYSKICYIVCPN-UHFFFAOYSA-L sodium succinate (anhydrous) Chemical compound [Na+].[Na+].[O-]C(=O)CCC([O-])=O ZDQYSKICYIVCPN-UHFFFAOYSA-L 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 238000010532 solid phase synthesis reaction Methods 0.000 description 1
- 229940055944 soliris Drugs 0.000 description 1
- 229940034810 soltamox Drugs 0.000 description 1
- 229940034345 sotret Drugs 0.000 description 1
- UNFWWIHTNXNPBV-WXKVUWSESA-N spectinomycin Chemical compound O([C@@H]1[C@@H](NC)[C@@H](O)[C@H]([C@@H]([C@H]1O1)O)NC)[C@]2(O)[C@H]1O[C@H](C)CC2=O UNFWWIHTNXNPBV-WXKVUWSESA-N 0.000 description 1
- 229960000268 spectinomycin Drugs 0.000 description 1
- 210000000278 spinal cord Anatomy 0.000 description 1
- 208000011584 spitz nevus Diseases 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 229940068117 sprycel Drugs 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 238000011272 standard treatment Methods 0.000 description 1
- 229960001203 stavudine Drugs 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 150000003431 steroids Chemical group 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 229960001052 streptozocin Drugs 0.000 description 1
- 229910052712 strontium Inorganic materials 0.000 description 1
- CIOAGBVUUVVLOB-UHFFFAOYSA-N strontium atom Chemical compound [Sr] CIOAGBVUUVVLOB-UHFFFAOYSA-N 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 238000009495 sugar coating Methods 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 206010042863 synovial sarcoma Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000007910 systemic administration Methods 0.000 description 1
- 238000012385 systemic delivery Methods 0.000 description 1
- 229940095374 tabloid Drugs 0.000 description 1
- ZMELOYOKMZBMRB-DLBZAZTESA-N talmapimod Chemical compound C([C@@H](C)N(C[C@@H]1C)C(=O)C=2C(=CC=3N(C)C=C(C=3C=2)C(=O)C(=O)N(C)C)Cl)N1CC1=CC=C(F)C=C1 ZMELOYOKMZBMRB-DLBZAZTESA-N 0.000 description 1
- 229960001603 tamoxifen Drugs 0.000 description 1
- UXXQOJXBIDBUAC-UHFFFAOYSA-N tandutinib Chemical compound COC1=CC2=C(N3CCN(CC3)C(=O)NC=3C=CC(OC(C)C)=CC=3)N=CN=C2C=C1OCCCN1CCCCC1 UXXQOJXBIDBUAC-UHFFFAOYSA-N 0.000 description 1
- 229910052715 tantalum Inorganic materials 0.000 description 1
- GUVRBAGPIYLISA-UHFFFAOYSA-N tantalum atom Chemical compound [Ta] GUVRBAGPIYLISA-UHFFFAOYSA-N 0.000 description 1
- 229940099419 targretin Drugs 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 229940069905 tasigna Drugs 0.000 description 1
- 229910052713 technetium Inorganic materials 0.000 description 1
- GKLVYJBZJHMRIY-UHFFFAOYSA-N technetium atom Chemical compound [Tc] GKLVYJBZJHMRIY-UHFFFAOYSA-N 0.000 description 1
- 229940061353 temodar Drugs 0.000 description 1
- 229960004964 temozolomide Drugs 0.000 description 1
- 229960000235 temsirolimus Drugs 0.000 description 1
- QFJCIRLUMZQUOT-UHFFFAOYSA-N temsirolimus Natural products C1CC(O)C(OC)CC1CC(C)C1OC(=O)C2CCCCN2C(=O)C(=O)C(O)(O2)C(C)CCC2CC(OC)C(C)=CC=CC=CC(C)CC(C)C(=O)C(OC)C(O)C(C)=CC(C)C(=O)C1 QFJCIRLUMZQUOT-UHFFFAOYSA-N 0.000 description 1
- 229960001278 teniposide Drugs 0.000 description 1
- 229960004556 tenofovir Drugs 0.000 description 1
- VCMJCVGFSROFHV-WZGZYPNHSA-N tenofovir disoproxil fumarate Chemical compound OC(=O)\C=C\C(O)=O.N1=CN=C2N(C[C@@H](C)OCP(=O)(OCOC(=O)OC(C)C)OCOC(=O)OC(C)C)C=NC2=C1N VCMJCVGFSROFHV-WZGZYPNHSA-N 0.000 description 1
- GZCRRIHWUXGPOV-UHFFFAOYSA-N terbium atom Chemical compound [Tb] GZCRRIHWUXGPOV-UHFFFAOYSA-N 0.000 description 1
- IWVCMVBTMGNXQD-UHFFFAOYSA-N terramycin dehydrate Natural products C1=CC=C2C(O)(C)C3C(O)C4C(N(C)C)C(O)=C(C(N)=O)C(=O)C4(O)C(O)=C3C(=O)C2=C1O IWVCMVBTMGNXQD-UHFFFAOYSA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 201000003120 testicular cancer Diseases 0.000 description 1
- 229960005353 testolactone Drugs 0.000 description 1
- BPEWUONYVDABNZ-DZBHQSCQSA-N testolactone Chemical compound O=C1C=C[C@]2(C)[C@H]3CC[C@](C)(OC(=O)CC4)[C@@H]4[C@@H]3CCC2=C1 BPEWUONYVDABNZ-DZBHQSCQSA-N 0.000 description 1
- 229960003604 testosterone Drugs 0.000 description 1
- 229960003433 thalidomide Drugs 0.000 description 1
- 229910052716 thallium Inorganic materials 0.000 description 1
- BKVIYDNLLOSFOA-UHFFFAOYSA-N thallium Chemical compound [Tl] BKVIYDNLLOSFOA-UHFFFAOYSA-N 0.000 description 1
- 229940034915 thalomid Drugs 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 229940033663 thimerosal Drugs 0.000 description 1
- 108010061238 threonyl-glycine Proteins 0.000 description 1
- 201000002510 thyroid cancer Diseases 0.000 description 1
- 229910052718 tin Inorganic materials 0.000 description 1
- 229960003087 tioguanine Drugs 0.000 description 1
- MNRILEROXIRVNJ-UHFFFAOYSA-N tioguanine Chemical compound N1C(N)=NC(=S)C2=NC=N[C]21 MNRILEROXIRVNJ-UHFFFAOYSA-N 0.000 description 1
- 229960000838 tipranavir Drugs 0.000 description 1
- SUJUHGSWHZTSEU-FYBSXPHGSA-N tipranavir Chemical compound C([C@@]1(CCC)OC(=O)C([C@H](CC)C=2C=C(NS(=O)(=O)C=3N=CC(=CC=3)C(F)(F)F)C=CC=2)=C(O)C1)CC1=CC=CC=C1 SUJUHGSWHZTSEU-FYBSXPHGSA-N 0.000 description 1
- 229910052719 titanium Inorganic materials 0.000 description 1
- 239000010936 titanium Substances 0.000 description 1
- OGIDPMRJRNCKJF-UHFFFAOYSA-N titanium oxide Inorganic materials [Ti]=O OGIDPMRJRNCKJF-UHFFFAOYSA-N 0.000 description 1
- 229940035307 toposar Drugs 0.000 description 1
- 229960000303 topotecan Drugs 0.000 description 1
- 229960005026 toremifene Drugs 0.000 description 1
- XFCLJVABOIYOMF-QPLCGJKRSA-N toremifene Chemical compound C1=CC(OCCN(C)C)=CC=C1C(\C=1C=CC=CC=1)=C(\CCCl)C1=CC=CC=C1 XFCLJVABOIYOMF-QPLCGJKRSA-N 0.000 description 1
- MFAQYJIYDMLAIM-UHFFFAOYSA-N torkinib Chemical compound C12=C(N)N=CN=C2N(C(C)C)N=C1C1=CC2=CC(O)=CC=C2N1 MFAQYJIYDMLAIM-UHFFFAOYSA-N 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- FGMPLJWBKKVCDB-UHFFFAOYSA-N trans-L-hydroxy-proline Natural products ON1CCCC1C(O)=O FGMPLJWBKKVCDB-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 238000010361 transduction Methods 0.000 description 1
- 230000026683 transduction Effects 0.000 description 1
- 239000012581 transferrin Substances 0.000 description 1
- 206010044412 transitional cell carcinoma Diseases 0.000 description 1
- 238000013519 translation Methods 0.000 description 1
- 230000005945 translocation Effects 0.000 description 1
- 210000003956 transport vesicle Anatomy 0.000 description 1
- PBKWZFANFUTEPS-CWUSWOHSSA-N transportan Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(C)C)C(N)=O)[C@@H](C)CC)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)CN)[C@@H](C)O)C1=CC=C(O)C=C1 PBKWZFANFUTEPS-CWUSWOHSSA-N 0.000 description 1
- 108010062760 transportan Proteins 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- 229960001727 tretinoin Drugs 0.000 description 1
- 229940111528 trexall Drugs 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- YKUJZZHGTWVWHA-UHFFFAOYSA-N triptolide Natural products COC12CC3OC3(C(C)C)C(O)C14OC4CC5C6=C(CCC25C)C(=O)OC6 YKUJZZHGTWVWHA-UHFFFAOYSA-N 0.000 description 1
- 229940086984 trisenox Drugs 0.000 description 1
- VEYYPTLVZZKRQR-UHFFFAOYSA-N trisodium methanetriolate Chemical compound C([O-])([O-])[O-].[Na+].[Na+].[Na+] VEYYPTLVZZKRQR-UHFFFAOYSA-N 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 231100000588 tumorigenic Toxicity 0.000 description 1
- 230000000381 tumorigenic effect Effects 0.000 description 1
- WFKWXMTUELFFGS-UHFFFAOYSA-N tungsten Chemical compound [W] WFKWXMTUELFFGS-UHFFFAOYSA-N 0.000 description 1
- 229910052721 tungsten Inorganic materials 0.000 description 1
- 239000010937 tungsten Substances 0.000 description 1
- 108010017949 tyrosyl-glycyl-glycine Proteins 0.000 description 1
- 208000022810 undifferentiated (embryonal) sarcoma Diseases 0.000 description 1
- 241000701161 unidentified adenovirus Species 0.000 description 1
- 241000712461 unidentified influenza virus Species 0.000 description 1
- 241001430294 unidentified retrovirus Species 0.000 description 1
- 238000011144 upstream manufacturing Methods 0.000 description 1
- DNYWZCXLKNTFFI-UHFFFAOYSA-N uranium Chemical compound [U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U] DNYWZCXLKNTFFI-UHFFFAOYSA-N 0.000 description 1
- 210000003932 urinary bladder Anatomy 0.000 description 1
- 206010046766 uterine cancer Diseases 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 238000009777 vacuum freeze-drying Methods 0.000 description 1
- MSRILKIQRXUYCT-UHFFFAOYSA-M valproate semisodium Chemical compound [Na+].CCCC(C(O)=O)CCC.CCCC(C([O-])=O)CCC MSRILKIQRXUYCT-UHFFFAOYSA-M 0.000 description 1
- 229960000604 valproic acid Drugs 0.000 description 1
- ZOCKGBMQLCSHFP-KQRAQHLDSA-N valrubicin Chemical compound O([C@H]1C[C@](CC2=C(O)C=3C(=O)C4=CC=CC(OC)=C4C(=O)C=3C(O)=C21)(O)C(=O)COC(=O)CCCC)[C@H]1C[C@H](NC(=O)C(F)(F)F)[C@H](O)[C@H](C)O1 ZOCKGBMQLCSHFP-KQRAQHLDSA-N 0.000 description 1
- SJSNUMAYCRRIOM-QFIPXVFZSA-N valsartan Chemical compound C1=CC(CN(C(=O)CCCC)[C@@H](C(C)C)C(O)=O)=CC=C1C1=CC=CC=C1C1=NN=N[N]1 SJSNUMAYCRRIOM-QFIPXVFZSA-N 0.000 description 1
- 229960004699 valsartan Drugs 0.000 description 1
- 229940054937 valstar Drugs 0.000 description 1
- 229940108442 valtrex Drugs 0.000 description 1
- 108010073969 valyllysine Proteins 0.000 description 1
- 229910052720 vanadium Inorganic materials 0.000 description 1
- GPPXJZIENCGNKB-UHFFFAOYSA-N vanadium Chemical compound [V]#[V] GPPXJZIENCGNKB-UHFFFAOYSA-N 0.000 description 1
- 229960000241 vandetanib Drugs 0.000 description 1
- UHTHHESEBZOYNR-UHFFFAOYSA-N vandetanib Chemical compound COC1=CC(C(/N=CN2)=N/C=3C(=CC(Br)=CC=3)F)=C2C=C1OCC1CCN(C)CC1 UHTHHESEBZOYNR-UHFFFAOYSA-N 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 229950011257 veliparib Drugs 0.000 description 1
- 208000008662 verrucous carcinoma Diseases 0.000 description 1
- 229960003895 verteporfin Drugs 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
- 229940061389 viadur Drugs 0.000 description 1
- 229960003048 vinblastine Drugs 0.000 description 1
- AQTQHPDCURKLKT-PNYVAJAMSA-N vincristine sulfate Chemical compound OS(O)(=O)=O.C([C@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C=O)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 AQTQHPDCURKLKT-PNYVAJAMSA-N 0.000 description 1
- GBABOYUKABKIAF-IELIFDKJSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-IELIFDKJSA-N 0.000 description 1
- 229960002066 vinorelbine Drugs 0.000 description 1
- CILBMBUYJCWATM-PYGJLNRPSA-N vinorelbine ditartrate Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O.OC(=O)[C@H](O)[C@@H](O)C(O)=O.C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC CILBMBUYJCWATM-PYGJLNRPSA-N 0.000 description 1
- 229940061392 visudyne Drugs 0.000 description 1
- WAEXFXRVDQXREF-UHFFFAOYSA-N vorinostat Chemical compound ONC(=O)CCCCCCC(=O)NC1=CC=CC=C1 WAEXFXRVDQXREF-UHFFFAOYSA-N 0.000 description 1
- 229940069559 votrient Drugs 0.000 description 1
- 201000004916 vulva carcinoma Diseases 0.000 description 1
- 208000013013 vulvar carcinoma Diseases 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- QDLHCMPXEPAAMD-UHFFFAOYSA-N wortmannin Natural products COCC1OC(=O)C2=COC(C3=O)=C2C1(C)C1=C3C2CCC(=O)C2(C)CC1OC(C)=O QDLHCMPXEPAAMD-UHFFFAOYSA-N 0.000 description 1
- 230000029663 wound healing Effects 0.000 description 1
- 210000005253 yeast cell Anatomy 0.000 description 1
- NAWDYIZEMPQZHO-UHFFFAOYSA-N ytterbium Chemical compound [Yb] NAWDYIZEMPQZHO-UHFFFAOYSA-N 0.000 description 1
- 229910052727 yttrium Inorganic materials 0.000 description 1
- VWQVUPCCIRVNHF-UHFFFAOYSA-N yttrium atom Chemical compound [Y] VWQVUPCCIRVNHF-UHFFFAOYSA-N 0.000 description 1
- 229960000523 zalcitabine Drugs 0.000 description 1
- ARAIBEBZBOPLMB-UFGQHTETSA-N zanamivir Chemical compound CC(=O)N[C@@H]1[C@@H](N=C(N)N)C=C(C(O)=O)O[C@H]1[C@H](O)[C@H](O)CO ARAIBEBZBOPLMB-UFGQHTETSA-N 0.000 description 1
- 229940053890 zanosar Drugs 0.000 description 1
- 229960002555 zidovudine Drugs 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 239000011787 zinc oxide Substances 0.000 description 1
- 229910052726 zirconium Inorganic materials 0.000 description 1
- 229940033942 zoladex Drugs 0.000 description 1
- 229940061261 zolinza Drugs 0.000 description 1
- 229940051084 zytiga Drugs 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/005—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from viruses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/10—Peptides having 12 to 20 amino acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/162—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from virus
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
- A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
- A61K47/60—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
- A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
- A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
- A61K47/641—Branched, dendritic or hypercomb peptides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N7/00—Viruses; Bacteriophages; Compositions thereof; Preparation or purification thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/01—Fusion polypeptide containing a localisation/targetting motif
- C07K2319/035—Fusion polypeptide containing a localisation/targetting motif containing a signal for targeting to the external surface of a cell, e.g. to the outer membrane of Gram negative bacteria, GPI- anchored eukaryote proteins
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/70—Fusion polypeptide containing domain for protein-protein interaction
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/70—Fusion polypeptide containing domain for protein-protein interaction
- C07K2319/74—Fusion polypeptide containing domain for protein-protein interaction containing a fusion for binding to a cell surface receptor
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2740/00—Reverse transcribing RNA viruses
- C12N2740/00011—Details
- C12N2740/10011—Retroviridae
- C12N2740/16011—Human Immunodeficiency Virus, HIV
- C12N2740/16022—New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2740/00—Reverse transcribing RNA viruses
- C12N2740/00011—Details
- C12N2740/10011—Retroviridae
- C12N2740/16011—Human Immunodeficiency Virus, HIV
- C12N2740/16311—Human Immunodeficiency Virus, HIV concerning HIV regulatory proteins
- C12N2740/16322—New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Organic Chemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Gastroenterology & Hepatology (AREA)
- Genetics & Genomics (AREA)
- Virology (AREA)
- Molecular Biology (AREA)
- Immunology (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- Wood Science & Technology (AREA)
- Zoology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Biotechnology (AREA)
- Biomedical Technology (AREA)
- Microbiology (AREA)
- General Engineering & Computer Science (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
Abstract
用于治疗癌症的方法包括对有需要这些治疗的个体投予有效量的医药组成物,其中该医药组成物是包括具有至少一个来自HIV‑1 Nef的分泌修饰区(SMR)胜肽的抗癌剂,且该SMR胜肽与至少一个细胞穿透胜肽(CPP)或至少一个凝聚素(Clusterin,Clu)结合胜肽(Clu‑BP)融合。
Description
本申请主张于2018年7月9日申请的美国第16/030,430号申请案的优先权。前述申请案的全文通过引用并于本文。
本申请是在NIH所授某些补助下政府支持进行。政府对本申请具有一定权利。
技术领域
本说明书通常是关于用于药物治疗的组成物及方法,且尤其是关于用于通过抑制胞外体(exosome)释放以治疗癌症及感染性疾病的方法。
背景技术
膜胞外体为球型膜微囊泡(microvesicle),直径通常小于200nm。胞外体由含有细胞溶质组分(cytosolic fraction)的脂质双层组成。更具体地,特定膜囊泡是通过细胞的细胞质膜融合而自细胞内区室产生,使其释放至生物体的细胞外生物液或细胞培养基中。这些胞外体可以多种方法释放。典型分泌路径主要是通过内质网(ER)膜处理具有受体的传统膜信号(Lee et al,(2004)Amur.Rev.Cell Dev.Biol.20,87-123)。
将分泌蛋白包装至运输囊泡中、递送至高基式体、并最终释放至细胞外空间中。替代地,非典型分泌路径是介导细胞质、非信号携带分子至细胞外空间的转移(Lippincott-Schwartz et al,(1989)Cell 56,801-813;and Misumi et al.,(1986)J.Biol.Chem.261,11398-11403)。其中二者是涵盖胞吞膜系统的细胞内囊泡,例如分泌性溶酶体(Muesch etal,(1990)Trends Biochem.Sci.15,86-88)以及胞外体(Johnstone et al.,(1987)J.Biol.Chem.262,9412-9420),后者为晚期胞内体(endosome)或多囊泡体(MVB)的内部囊泡。当特殊的胞吞结构(例如胞毒性T淋巴球的分泌性溶酶体)与细胞膜融合时,溶酶体内容物得以抵达细胞外部。当MVBs与细胞膜融合时,晚期胞吞结构的腔内容物释放至细胞外空间,使得内部多囊泡胞内体与其所载分子释放至细胞外空间(称为胞外体)。其他非典型路径涵盖使用蛋白质传导通道或称为细胞膜起泡(membrane blebbing)的过程以将细胞质因子跨过细胞膜直接转移(Nickel,W.(2005)Traffic.6,607-614)。细胞膜起泡的特征在于其是将细胞膜衍生的微囊泡排出到细胞外空间。
已在不同的生理环境中自不同的细胞类型证明了胞外体释放。已证明肿瘤细胞分泌胞外体,例如以受调控的方式分泌胞外体,其可携带可呈现给抗原呈现细胞的肿瘤抗原(专利申请号为WO99/03499)。此外,已知含有FasL或TNF的胞外体会造成可促进肿瘤生长的免疫豁免(immune privilege)/免疫抑制状态。类似地,已知受病毒感染的细胞(包括感染HIV的细胞)释放含有Nef的胞外体(Guy et al,(1990)Virology 176,413-425;andCampbell et al,(2008)Ethn.Dis.18,S2-S9),其是用于抑制免疫系统使得HIV存活。已显示胞外体的分泌是利用与感染细胞中病毒体释放相关的相同胞内体运输路径(Sanfridsonet al,(1997)Proc.Natl.Acad.Sci.U.S.A 94,873-878;and Esser et al.,(2001)JVirol.75,6173-6182)。
已知肿瘤细胞释放大量胞外体,其可通过杀死免疫细胞或使之失调来造成免疫抑制,进而促进了使得肿瘤快速生长的免疫抑制状态(Lindner K.et al.,2015,Salido-Guadarrama I.et al,2014)。类似地,HIV感染导致大量胞外体,其似乎有助于免疫豁免/抑制状态,最终可能导致后天免疫不全症候群(AIDS)。胞外体分泌路径涵盖于调节癌症衡定、免疫系统及经感染细胞的病毒体释放中。鉴于前述内容,本领域需要用于抑制胞外体释放的组成物及有效治疗方法。
发明内容
本说明书的一方面是关于抑制来自细胞的胞外体释放的多部分胜肽(multipartite peptide)。该胜肽含有至少一个来自HIV-1Nef的分泌修饰区(SMR)胜肽、以及至少一个凝聚素(Clusterin,Clu)结合胜肽(Clu-BP)及/或细胞穿透胜肽(CPP)。
在一实施方案中,用于治疗癌症的方法包括对有需要该治疗的个体投予有效量的医药组成物,其中该医药组成物包括抗癌剂,该抗癌剂具有至少一个来自HIV-1Nef的分泌修饰区(SMR)胜肽,且该胜肽与至少一个细胞穿透胜肽(CPP)或至少一个凝聚素(Clu)结合胜肽(Clu-BP)融合。
在一实施方案中,该SMR胜肽与至少一个CPP融合。在另一实施方案中,该SMR胜肽与2、3、4或5个CPP序列融合。在一特定实施方案中,该胜肽在其N端终端具有SMR胜肽模体且在其C端终端具有CPP胜肽模体。在另一实施方案中,该胜肽在其N端终端具有CPP胜肽且在其C端终端具有SMR胜肽。
在另一实施方案中,该SMR胜肽与至少一个Clu-BP融合。在另一实施方案中,该SMR胜肽包括2、3、4或5个Clu-BP序列。在一特定实施方案中,该胜肽在其N端终端具有SMR胜肽模体且在其C端终端具有Clu-BP胜肽模体。在另一实施方案中,该胜肽在其N端终端具有Clu-BP胜肽且在其N端终端具有SMR胜肽。
在另一实施方案中,该SMR胜肽具有至少一个CPP及至少一个Clu-BP。
在一实施方案中,该SMR胜肽具有一个选自由以下组成的群组的胺基酸序列:VGFPV(SEQ ID NO:1)、VGFPVAAVGFPV(SEQ ID NO:2)、VGFPVAAVGFPVHPLSKHPYWSQP(SEQ IDNO:6)、VGFPVAAVGFPVAAHPLSKHPYWSQP(SEQ ID NO:7)、VGFPVAAVGFPVAAHPLSKHPYWSQPAAHPLSKHPYWSQP(SEQ ID NO:8)、NXNVGFPVAAVGFPV(SEQ ID NO:36)、NXNVGFPVAAVGFPVHPLSKHPYWSQP(SEQ ID NO:37)、及VGRKKRRQRRRPPQ(SEQ ID NO:39)。
在另一实施方案中,该至少一个CPP包括胺基酸序列GRKKRRQRRRPPQ(SEQ ID NO:38)。
在部分实施方案中,该至少一个Clu-BP包括选自由以下组成的群组的胺基酸序列:HPLSKHPYWSQP(SEQ ID NO:3)、NTYWSQLLHFQT(SEQ ID NO:4)、及SHALPLTWSTAA(SEQ IDNO:5)。
在一实施方案中,该个体具有乳癌。
在另一实施方案中,该个体具有白血病。
在另一实施方案中,该方法进一步包括对该个体投予第二抗癌剂的步骤。
在一特定实施方案中,该第二抗癌剂为紫杉醇(paclitaxel)或顺铂(cisplatin)。
在另一实施方案中,该第二抗癌剂为致死蛋白(mortalin)抑制剂。
在一特定实施方案中,该致死蛋白抑制剂为MKT-077、奥美拉唑、或5-(N,N-二甲基)阿米洛利(5-(N,N-dimethyl)amiloride,DMA)。
在另一方面,多核苷酸编码本文描述的多部分胜肽。
在一实施方案中,该多核苷酸可操控地连接至调节序列的表现载体。
在另一实施方案中,细胞包括表现载体。
在另一方面,医药组成物包括抗癌剂,其中该抗癌剂包括至少一个来自HIV-1Nef的分泌修饰区(SMR)胜肽,且该胜肽与至少一个细胞穿透胜肽(CPP)或至少一个凝聚素(Clu)结合胜肽(Clu-BP)融合。
在一实施方案中,该医药组成物进一步包括第二抗癌剂。
在一更特定的实施方案中,该第二抗癌剂选自由以下组成的群组:致死蛋白(Hsp70)抑制剂、烷化剂、蒽环抗生素、抗代谢物、解毒剂、干扰素、多株(polyclonal)或单株抗体、EGFR抑制剂、HER2抑制剂、组蛋白去乙酰酶抑制剂、荷尔蒙或抗荷尔蒙剂、有丝分裂抑制剂、磷脂酰肌醇3-激酶(PI3K)抑制剂、Akt抑制剂、哺乳动物标靶的雷帕霉素(mTOR)抑制剂、蛋白酶体抑制剂、聚(ADP-核糖)聚合酶(PARP)抑制剂、Ras/MAPK路径抑制剂、中心体解簇剂(centrosome declustering agent)、多激酶抑制剂、丝胺酸/苏胺酸激酶抑制剂、酪胺酸激酶抑制剂、VEGF/VEGFR抑制剂、紫杉烷或紫杉烷衍生物、芳香酶抑制剂、蒽环类药物、微管标靶药物、拓朴异构酶毒药、及前述的组合。
在另一实施方案中,该多部分胜肽为聚乙二醇化的。在另一实施方案中,该多部分胜肽并入奈米颗粒中、并于奈米颗粒上、或者与奈米颗粒连接。在某些特定实施方案中,该奈米颗粒连接至CPP胜肽。
附图说明
根据结合附图及段落来考虑以下详细描述,本申请的上述及其他目的与优点为显而易见的。以下是本文附图的简要描述,其说明本申请的某些方面及实施方案,但无论如何不能视为限制。
图1显示SMRwt胜肽拮抗剂抑制了MCF-7及MDA-MB-231乳癌细胞的增殖,但不抑制非致瘤细胞(non-tumorigenic cell)。将细胞与各种剂量(0-1120nM)的胜肽进行培养24小时,而后通过MTT试验测量细胞增殖。显示了三次独立实验的结果。图表A:MCF-7乳癌细胞的增殖。图表B:MDA-MB-231乳癌细胞的增殖。图表C:非致瘤MCF-10A细胞的增殖。红色圆点表示PEG-SMRwt胜肽、黑色圆点表示PEG-SMRwt-CLU胜肽、及绿色三角形表示PEG-SMRmut胜肽。
图2显示在MCF-7及MDA-MB-231乳癌细胞中PEG-SMRwt-CLU胜肽拮抗剂及化疗诱导细胞周期停滞。将细胞与SMR胜肽单独、或与SMR胜肽结合紫杉醇或顺铂进行处理48小时,并通过Cellometer成像细胞仪进行试验,表示在不同细胞周期相的MCF-7(图表A)及MDA-MB-231(图表B)的百分比。显示了两次独立实验的结果。相对于未处理对照的显著差异表示如下:对于MCF-7细胞,*p<0.01、**p<0.001;及对于MDA-MB-231细胞,*p<0.02、**p<0.01、***p<0.0001。
图3显示在MCF-7中PEG-SMRwt-CLU胜肽拮抗剂提升了细胞毒性,但在MDA-MB-231乳癌细胞中则否。MCF-7(图表A)及MDA-MB-231(图表B)细胞凋亡的百分比是在细胞单独经胜肽、或胜肽结合紫杉醇或顺铂处理后通过Annexin V-FITC试验确定。误差杠表示四次独立实验的平均值±SD。相对于SMRwt胜肽的显著差异表示如下:*p<0.01、**p<0.001。
图4显示PEG-SMRwt-CLU胜肽拮抗剂阻挡了胞外体自MCF-7及MDA-MB-231细胞中释放。细胞单独经胜肽、或胜肽结合紫杉醇或顺铂进行处理48小时。图表A及B显示分别自MCF-7及MDA-MB-231细胞中释放的胞外体相对数量,其通过AchE试验确定。误差杠表示四次独立实验的平均值±SD。相对于SMRwt胜肽的显著差异表示如下:对于MCF-7细胞,*p<0.01、**p<0.001、***p<0.0001;及对于MDA-MB-231细胞,*p<0.01。图表C及D显示分别自MCF-7及MDA-MB-231细胞中释放的胞外体相对数量,其通过Nanosight测量确定。误差杠表示两次独立实验的平均值±SD。相对于SMRwt胜肽的显著差异表示如下:对于MCF-7细胞,*p<0.01、**p<0.001、***p<0.0001;及对于MDA-MB-231细胞,*p<0.03、**p<0.02、***p<0.01、****p<0.001。
图5显示可以自MCF-7乳癌细胞的胞外体中检测出胞外体特异蛋白质。细胞单独经SMRwt胜肽、或SMRwt胜肽结合紫杉醇或顺铂进行处理48小时。图表A:通过西方墨点分析的胞外体蛋白质表现。图表B:通过Nanosight测量的胞外体数量。图表C:密度分析显示条带(band)的相对强度。数据表示三次独立实验的平均值±SD。相对于胜肽处理的显著差异表示如下:*p<0.01、**p<0.001、***p<0.0001。
图6显示可在来自MDA-MB-231乳癌细胞的胞外体上检测出胞外体特异蛋白质。细胞单独经SMRwt胜肽、或SMRwt胜肽结合紫杉醇或顺铂进行处理48小时。图表A显示通过西方墨点分析的胞外体蛋白质表现。通过NanoSight测量胞外体数量(图表B)及密度分析显示条带的相对强度(图表C)。数据表示三次独立实验的平均值±SD。相对于胜肽处理的显著差异表示如下:*p<0.01、**p<0.001、****p<0.0001。
图7显示致死蛋白抗体抑制来自MCF-7乳癌细胞的胞外体分泌。MCF-7细胞经致死蛋白抗体或α-微管蛋白(α-tubulin)转染、或者经SMRwt或SMRmut胜肽处理。图表A:通过AchE试验的48小时后的胞外体相对释放水平。图表B:通过NanoSight分析的48小时后释放的胞外体相对数量。误差杠表示三次独立实验的平均值±SD。相对于未处理细胞的显著差异表示如下:*p<0.0001、**p<0.0001。
图8显示通过剔除(knockdown)致死蛋白表现的基因降低了在MCF-7乳癌细胞中的胞外体分泌。将MCF-7细胞使用表现针对抗致死蛋白(HSPA9)或将阴性对照RNA的siRNA选殖株进行转染。在24、48、72及96小时后分离胞外体并通过AchE试验分析胞外体分泌水平的改变(图表A)。对于N-Rh-PE的胞外体分泌,相对于对照的显著差异表示如下:***p<0.0001(图表B)。相对于对照的显著差异表示如下:***p<0.0001。图表C:在各个时间点残留的活细胞百分比,*p<0.05、**p<0.002、***p<0.0001。图表D:通过西方墨点法的致死蛋白及CD63蛋白质表现。图表E:西方墨点法数据的密度分析。相对于对照的显著差异表示如下:*p<0.01、**p<0.001、***p<0.0001。
图9的图表A显示图8-14所述的用于实验的合成SMRwt-CPPtat(SEQ ID NO:39)及SMRmut-CPPtat(SEQ ID NO:41)胜肽。图表B显示图8-14所述的用于实验的合成SMRwt-CluBP(SEQ ID NO:37)及SMRmut-Clu BP(SEQ ID NO:43)胜肽。该SMRwt胜肽在全部的HIV-1分支群、HIV-2、及SIV中为高度保守。在图表B中,该胜肽在天冬酰胺内肽酶的剪切位点上游的N端进一步包括聚乙二醇部分。
图10显示SMRwt-CPP胜肽减少了MCF-7及MDA-MB-231乳癌细胞及K562白血病细胞的增殖,但非致瘤MCF-10A细胞则否。细胞与不同剂量(0-1120nM)的胜肽在37℃下培养24小时,而后通过MTT试验测量增殖。三次独立实验的结果显示于图表A-D。图表A显示IC50为180nM/mL的MCF-7乳癌细胞的增殖减少;图表B显示IC50为476nM/mL的MDA-MB-231乳癌细胞的增殖减少;图表C显示在作为对照细胞的非致瘤MCF-10A细胞增殖上无影响;图表D显示IC50为907nM/mL的K562白血病细胞的增殖减少。该图表A、B及D中减少的增殖仅在野生型SMR存在下观察到,在突变SMR存在下则否。
图11显示使用PEG-SMRwt-Clu胜肽、SMRwt-CPP胜肽、或致死蛋白抑制剂、MKT-077、奥美拉唑、或5-(N,N-二甲基)阿米洛利(DMA)拮抗剂治疗的MCF-7乳癌细胞、MDA-MB-231乳癌细胞及K562白血病细胞胞外体释放被阻挡。这些三种细胞型各自使用PEG-SMRwt-Clu胜肽、PEG-SMRmut-Clu胜肽、SMRwt-CPP胜肽、SMRmut-CPP胜肽、MKT-077、奥美拉唑或DMA在37°C下进行处理五天。图表A、B及C分别显示来自MCF-7细胞、MDA-MB-231细胞、及K562细胞的胞外体释放水平,其通过乙酰胆碱酯酶(acetylcholinesterase,AChE)试验确定。
图12显示在自MCF-7乳癌细胞、MDA-MB-231乳癌细胞及K562白血病细胞释放的胞外体中的致死蛋白、波形蛋白(vimentin)及胞外体特异ALIX蛋白质检测,其中这些细胞使用PEG-SMRwt-Clu、PEG-SMRmut-Clu、SMRwt-CPP、SMRmut-CPP、MKT-077、奥美拉唑或DMA在37℃下进行处理48小时。使用抗致死蛋白(Grp-75)、抗波形蛋白及抗Alix抗体进行西方墨点法分析,以评估致死蛋白、波形蛋白及胞外体表现。图表A显示在MCF-7及MDA-MB-231乳癌细胞及K562白血病细胞中的胞外体产物、致死蛋白、波形蛋白及Alix的胶体影像;图表B显示在MCF-7及MDA-MB-231乳癌细胞及K562白血病细胞中的胞外体产物、致死蛋白、波形蛋白及Alix的条带强度。通过相对条带强度的密度分析获得西方墨点法的量化结果。所示数据表示三次独立实验的平均值±SD。相对于胜肽处理的显著差异表示如下:*p<0.01、**p<0.001、***p<0.0001、****p<0.00001、*****p<0.000001、******p<0.0000001、*******p<0.00000001、********p<0.000000001。
图13显示在癌细胞中致死蛋白抑制剂MKT-077、DMA及奥美拉唑、及紫杉醇-(Pac)或顺铂(Cis)-诱导的癌细胞凋亡的影响。细胞经以下处理48小时:对MDA-MB-231细胞使用925nM/mL的MKT-077处理、对MCF-7细胞使用500nM/mL的MKT-077处理、对K562细胞使用337.5nM/mL的MKT-077处理、300μM/mL的DMA、200μM/mL的奥美拉唑、1.6μM/mL的紫杉醇、2mM/mL的顺铂、或三个致死细胞抑制剂各自与紫杉醇或顺铂的结合处理。MDA-MB-231细胞的细胞凋亡的相对水平;图表B是MCF-7细胞的细胞凋亡的相对水平;图表C是K562白血病细胞的细胞凋亡的相对水平,其通过TUNEL试验确定。误差杠表示四次独立实验的平均值±SD。相对于抑制剂的显著差异表示如下:分别为相对于DMA对DMA结合紫杉醇、以及奥美拉唑对奥美拉唑结合紫杉醇、及奥美拉唑结合顺铂,其表示如下:对MDA-MB-231细胞,**p<0.002、***p<0.0002、*****p<3.68E-06;分别为MKT-077对MKT-077结合紫杉醇、DMA对DMA结合顺铂、奥美拉唑对奥美拉唑结合顺铂,其表示如下:对MCF-7细胞,***p<0.0001、****p<6.18E-05、*****p<7.75E-08;奥美拉唑对奥美拉唑结合顺铂于K562表示为***p<0.0009。
图14显示在NHS、PEG-SMRwt-Clu及SMRwt-CPP胜肽存在下,SMRwt胜肽阻挡了致死蛋白及胞外体的分泌,并且在K562、MCF-7及MDA-MB-231培养中诱导了补体介导的细胞毒性。细胞单独使用280nM的PEG-SMRwt-Clu胜肽或560nM的SMRwt-CPP胜肽在37℃下处理60分钟,而后使用1μg/mL的抗CXCR4抗体及50μL的NHS或NIS在37℃下再处理60分钟。使用PEG-SMRmut-Clu胜肽及SMRmut-CPP胜肽作为阴性对照。经染色(死亡)细胞的百分比代表3次独立实验。图表A-C显示幸存于补体攻击的细胞的相对水平,其通过台酚蓝排除法确定。图表A显示MCF-7乳癌细胞治疗后的细胞存活百分比(如所示);图表B显示MDA-MB-231乳癌细胞治疗后的细胞存活百分比;以及,图表C显示K562白血病细胞治疗后的细胞存活百分比。细胞毒性未于单独使用SMR胜肽处理的细胞中观察到。误差杠表示四次独立实验的平均值±SD。相对于PEG-SMRwt-Clu胜肽及SMRwt-CPP胜肽的显著差异表示如下:*p<0.01、**p<0.001。
图15显示在K562、MCF-7及MDA-MB-231细胞培养中剔除致死蛋白的表现诱导了补体介导的细胞毒性。细胞使用表现双股致死蛋白siRNAs的载体进行转染。图表A显示致死蛋白及α-微管蛋白的检测,其使用抗致死蛋白及抗α-微管蛋白抗体进行SDS-PAGE/西方墨点法分析;图表B显示对应于图表A所检测的产物的相对条带强度;图表C显示MCF-7、MDA-MB-231及K562细胞释放的胞外体的相对数量,其通过NanoSight测量来确定;图表D显示致死蛋白表现(HSPA9)的siRNA介导基因剔除在正常人类血清(NHS)存在下诱导了补体介导的细胞毒性,但在热失活血清(HIS)存在下则否,或者在空载体转染细胞中或在表现非致死蛋白siRNA(Neg(“Neg”指经预测不会标靶任何已知脊椎动物基因的siRNA))的细胞中,无论是否存在NHS也无前述现象。相对于使用NHS的siRNA-Neg转染细胞及使用NHS处理的致死蛋白siRNA转染细胞的显著差异表示如下:*p<0.01、**p<0.001。
图16显示使用SMRwt胜肽处理MDA-MB-231及MCF-7乳癌细胞降低了其迁徙能力,然而非致瘤MCF-10A乳腺细胞的治疗不影响其迁徙能力。MDA-MB-231及MCF-7细胞经以下处理24小时:在MCF-7细胞中使用1120nM的SMR胜肽、在MDA-MB-231细胞中使用280nM的SMR胜肽、或使用3μM的红海海绵蛋白(Latrunculin A)作为对照,并且细胞迁徙试验使用荧光读盘仪(fluorescence plate reader)设定激发波长为485nm、发射波长为515nm且根据制造商说明(Calbiochem手册)来进行。图表A、B及C显示从以下细胞的迁徙的相对荧光单位:图表A:MCF-7乳癌细胞;图表B:MDA-MB-231乳癌细胞;以及,图表C:MCF-10A非致瘤乳腺细胞。误差杠表示四次独立实验的平均值±SD。相对于SMRwt胜肽的显著差异表示如下:*p<0.01、***p<0.0001、****p<0.00001、*****p<0.000001。
实施方式
除非另外定义,否则本文使用的全部技术及科学术语具有与公开方法及组成物的所属领域技术人员通常理解的相同含义。应注意,除非文中另有明确说明,否则如本文及后附申请专利范围中所使用的单数形式“一(a、an)”及“该”包括复数。因此,举例言之,提及“一个胜肽”包括“一或多个”胜肽或“复数个”这些胜肽。关于本申请中的教导,本申请中描述的任何已核准专利或专利申请公开本通过引用明确地并入本文中。此外,在使用词组“在部分实施方案中…”或“在某些实施方案中…”的情况下,除非这些特征与另一个特征的组合为相互排斥的、或在此明确声明放弃的,否则本说明书应被解释为包括定义本文所述的不同实施方案的任何特征的组合。
定义
如本文所使用,术语“SMR胜肽”及“SMRwt胜肽”指长度少于100个胺基酸的胜肽,其包括一套或多套(copy)的胺基酸序列VGFPV(SEQ ID NO:1)。术语“SMRmut胜肽”指长度少于100个胺基酸的胜肽,其包括一套或多套的经突变VGFPV胜肽序列,且废除了SMRwt胜肽的功能能力。
如本文所使用,词组“抗癌剂”指“小分子药物”、蛋白质、或抗体,其可在个体(例如人类)中减少癌细胞生长速度、或者诱导或介导癌细胞死亡(例如细胞坏死或细胞凋亡)。该词组“小分子药物”指分子实体,通常为有机的或有机金属的、不是聚合物,其具有药物活性、且具有小于约2kDa、小于约1kDa、小于约900Da、小于约800Da或小于约700Da的分子量。虽然小胜肽或核酸类似物也可被视为小分子药物,该术语包括蛋白质或核酸以外的大部分称为“药物”的药用化合物。例子包括化疗抗癌药及酶抑制剂。小分子药物可衍生自合成、半合成(即,自天然存在的前驱物)、或生物来源。
如本文所使用,术语“奈米颗粒”指具有平均直径少于500奈米(nm)的任何颗粒。在部分实施方案中,奈米颗粒具有少于300nm、少于100nm、少于50nm、少于25nm、少于10nm或少于5nm的平均直径。在部分实施方案中,各个奈米颗粒具有少于300nm、少于100nm、少于50nm、少于25nm、少于10nm或少于5nm的直径。
如本文所使用,术语“治疗(treat、treatment)”指改善与疾病(例如癌症或感染性疾病)相关的一种或多种症状;预防或延迟一种或多种疾病症状的发作;及/或减轻疾病的一种或多种症状的严重程度或频率。
术语“癌症”指多种恶性肿瘤中的任何一种,其特征在于具有侵袭周遭组织及/或迁徙至新定殖位点的能力的细胞增殖,且包括白血病、淋巴瘤、癌、黑色素瘤、肉瘤、生殖细胞肿瘤及胚胎细胞瘤。使用本说明书的方法治疗的例示性癌症包括脑癌、膀胱癌、乳癌、子宫颈癌、结肠癌、头颈癌、肾癌、肺癌、非小细胞肺癌、间皮瘤、卵巢癌、前列腺癌、胃癌及子宫癌、白血病及骨髓母细胞瘤。
术语“感染性疾病”包括由侵入及破坏哺乳动物体正常功能的病毒、细菌、真菌及/或寄生虫所引起的这些病理状况。第13版Merck手册的第3-147页描述了部分这些状态,并通过引用将其并入本文中。
词组“有需要的病患”、“有需要治疗的病患”或“有需要治疗的个体”包括受益于投予本说明书上述多部分胜肽来治疗细胞增生性失调的个体,例如哺乳动物个体。
术语“治疗有效量”、“药理学有效量”及“生理学有效量”可互换使用,表示在血流中或在标靶组织中提供阈值水平的活性拮抗剂所需的多部分胜肽的量。精确的量取决于许多因素,例如特定的活性剂、组成物的组分及物理特征、预期的病患群体、病患考虑因素等,并可以由本领域技术人员基于本文提供的信息或自相关文献中可获得的信息容易地确定。
在文中使用的术语“改善”、“增加”、或“减少”表示相对于基线测量的值或参数,例如:在开始本文所述治疗之前在同一个体中的测量结果、或在没有本文所述治疗的情况下在一个对照个体(或多个对照个体)中的测量结果。
“对照个体”指罹患与治疗中的个体相同疾病的个体,其与被治疗个体的年龄大致相同(以确保被治疗个体及对照个体的疾病阶段具有可比性)。被治疗个体(也称为“病患”或“受试者”)可为罹患细胞增生性失调的胎儿、婴儿、儿童、青少年或成人。
“小分子”指非聚合物的有机或无机分子,其具有药用活性且具有少于1kDa的分子量。该术语包括除了蛋白质或核酸(即使小分子胜肽或核酸类似物可被认为是“小分子”)的外称为“药物”的大部分药物化合物。小分子药物可以合成、半合成(即,来自天然存在的前驱物)或生物来源。如本文使用,词组“大分子”指基于聚合物蛋白质或核酸的产物,其分子量大于1kDa。
胜肽
本说明书之一方面是关于抑制胞外体自细胞中释放的多部分抗癌胜肽。在一实施方案中,该胜肽包括至少一个来自HIV-1Nef的分泌修饰区(SMR)胜肽、以及至少一个凝聚素(Clu)结合胜肽(Clu-BP)或至少一个细胞穿透胜肽(CPP)。
在部分实施方案中,该多部分抗癌胜肽具有1、2、3、4或5个SMR胜肽序列。在特定实施方案中,该SMR胜肽包括选自由以下组成的群组的胺基酸序列:VGFPV(SEQ ID NO:1)、VGFPVAAVGFPV(SEQ ID NO:2)、及NXNV GFPV AAV GFPV(SEQ ID NO:36)。
在一实施方案中,该SMR胜肽与至少一个Clu-BP融合。在另一实施方案中,该SMR胜肽包括2、3、4或5个Clu-BP序列。在一特定实施方案中,该胜肽在其N端终端具有SMR胜肽模体且在其C端终端具有Clu-BP胜肽模体。在另一实施方案中,该胜肽在其N端终端具有Clu-BP胜肽且在其C端终端具有SMR胜肽。
在部分实施方案中,该至少一个Clu-BP包括选自由以下组成的群组的胺基酸序列:HPLSKHPYWSQP(SEQ ID NO:3)、NTYWSQLLHFQT(SEQ ID NO:4)、及SHALPLTW STAA(SEQ IDNO:5),其如美国第2012/0121507号专利公开所述。
在另一实施方案中,该SMR胜肽与至少一个CPP融合。CPP区域增加了多部分胜肽进入真核细胞中。用于本申请的例示性的CPP区域包括但不限于,HIV TAT9-57胜肽、HIVTAT48-6O胜肽(SEQ ID NO:38)、低分子量鱼精蛋白(LMWP)胜肽、ChariotTM(也称为Pep-l)(Morris et al,Nat.Biotechnol,19:1173-1176,2001);Antp49-57胜肽、MPG(HIV Gp4l-SV40NLS)、SAP、MPG R9、MAP、K-FGF、穿透素(Penetratin)、抗菌肽(Buforin)II、转运子(Transportan)、Ku70、普恩蛋白(Prion)、pVEC、Pep-l-K、Pep-7、HN-l、TP10、及CP26(参见例如Joliot et al,Nature Cell Biol.,6(3):l 89-l96,2004及Heitz et al.,Br.J.Pharmacol.,157:195-206,2009)。
在一实施方案中,SMR胜肽与2、3、4或5个CPP序列融合。在一特定实施方案中,该胜肽在其N端终端具有SMR胜肽模体且在其C端终端具有CPP胜肽模体。在另一实施方案中,该胜肽在其N端终端具有CPP胜肽且在其C端终端具有SMR胜肽。
在一特定实施方案中,该至少一个CPP包括胺基酸序列GRKKRRQRRRPPQ(SEQ IDNO:38)。
在某些实施方案中,该胜肽具有至少两个SMR胜肽、至少两个Clu-BP胜肽、及/或至少两个CPP胜肽。此外,在SMR胜肽内的任何胜肽(例如SMR胜肽、Clu-BP胜肽、CPP胜肽)可通过间隔胜肽分开。
在某些特定实施方案中,该胜肽包括选自由以下组成的群组的胺基酸序列:VGFPVAAVGFPVHPLSKHPYWSQP(SEQ ID NO:6)、VGFPVAAVGFPVAAHPLSKHPYWSQP(SEQ ID NO:7)、VGFPVAAVGFPVAAHPLSKHPYWSQPAAHPLSKHPYWSQP(SEQ ID NO:8)、NXNVGFPVAAVGFPV(SEQID NO:36)、NXNVGFPVAAVGFPVHPLSKHPYWSQP(SEQ ID NO:37)、及VGRKKRRQRRRPPQ(SEQ IDNO:39)。
在某些实施方案中,本发明的多部分胜肽在多部分胜肽内的一个或多个功能区域之间进一步包括一个或多个间隔物(spacer)。设计间隔物以促进各个区域相对于彼此独立地折叠,确保所述胜肽中的各个区域不会彼此干扰或者不会干扰SMR胜肽及/或增加蛋白质的挠性且促进采用延展构象(extended conformation)。在部分实施方案中,该间隔物包括1至50个胺基酸,较佳为2至10个胺基酸。
在部分实施方案中,该间隔物包括一个或多个甘胺酸及/或丝胺酸残基,以迫使间隔物采回路构象,因为缺少β-碳使得多胜肽骨架接近对其他胺基酸而言在能量上不允许的二面角。此外,包括甘胺酸及/或丝胺酸的间隔物对于两个胜肽连接具有高自由度,即,其使得融合蛋白质折叠并制造功能性蛋白质。可增强稳定性及折叠的其他残基包括以下胺基酸:丙胺酸、脯胺酸、离胺酸、及前述的组合。在一实施方案中,该间隔物是Ala-Ala二胜肽连接子。在另一实施方案中,该间隔物具有式[(Gly)n-Ser/Ala]m,其中n为1至4(包括端点值),m为1至4(包括端点值)。
在部分实施方案中,该多部分胜肽包括粒线体穿透序列或粒线体标靶信号序列,以促进多部分胜肽进入致死蛋白所在的粒线体中。例示性的粒线体标靶序列包括美国第2004/0192627号专利公开所述的前序列胜肽(presequence peptide),包括核编码的人类细胞色素c氧化酶(COX)亚基VIII(MSVLTPLLLRGLTGSARRLPVPRAKIHSL(SEQ ID NO:9));大鼠鸟胺酸转胺甲酰酶(OTC)的胺基末端前导胜肽(MLSNLRILLNKAALRKAHTSMVRNFRYGKPVQC(SEQID NO:10)),细胞色素氧化酶亚基IV的前序列(MLSLRQSIRFFKPATRTL(SEQ ID NO:11))及触角足(Antennapedia)α-螺旋区域,例如RQIKIWFQNRRMKWKK(SEQ ID NO:12);美国第2014/0196172号专利公开所述的各种粒线体标靶胜肽,包括N-端粒线体标把胜肽,MFSYLPRYPLRAASARALVRATRPSYRSALLRYQ(SEQ ID NO:13)、MAAWMRSLFSPLKKLWIRMH(SEQ ID NO:14)、MKLLWRLILSRKW(SEQ ID NO:15)、MWWRRSRTNSLRYT(SEQ ID NO:16)、及MLFRLRRSVRLRGLLA(SEQ ID NO:17);以及,如美国第2016/0237129号专利公开所述的N-端粒线体标靶胜肽MWTLGRRAVAGLLASPSPAQ(SEQ ID NO:18)。引导蛋白质或胜肽至粒线体的例示性粒线体标靶信号胜肽序列包括RRIVVLHGY GAVKEVLLNHK(SEQ ID NO:19)、大鼠细胞色素P450 2E1(CYP2E1)的胺基酸74-95、来自酵母菌的细胞色素c氧化酶IV前驱物的可剪切前片段(prepiece)((MLSLRQDIRFFKPATRTLCSSR(SEQ ID NO:20))、来自流感病毒的PB2蛋白的粒线体标靶信号、血红素裂解酶中所含输入信号(import signal)、以及如美国第2014/0142121号专利公开所述的粒线体基质酶鸟胺酸转胺甲酰酶(OTC)的前导胜肽。
在部分实施方案中,该多部分胜肽可包括细胞标靶区域,其用于将该胜肽标靶至特定类型的细胞,包括肿瘤细胞、病毒感染的细胞等。标靶区域可包括与多部分胜肽融合的胜肽、或者可为与其化学偶联或共价连接的非肽基区域。例示性标靶区域包括胜肽、小分子、配体、抗体片段及适体。此外,标靶区域可为小分子(例如叶酸、腺苷、嘌呤)或特异性地结合至所需标靶细胞的大分子(例如胜肽或抗体)。在部分实施方案中,该标靶区域存在于该多部分胜肽的C-端终端。在其他实施方案中,该标靶区域存在于该多部分胜肽的N-端终端。
在部分实施方案中,该多部分胜肽包括血脑屏障(BBB)进入胜肽。包括BBB进入胜肽有助于将SMR胜肽递送至大脑以治疗脑癌(例如成神经胶质母细胞瘤)。例示性的BBB进入胜肽包括GGGGHLNILSTLWKYRC(SEQ ID NO:45;美国第2018/0073021号专利公开)、TFFYGGSRGKRNNFKTEEYC(SEQ ID NO:46;Wang et al,Scient.Rep.(2018)8:12827)、RRRRRRRR(SEQ ID NO:47;Kamei et al.,Biol.Pharm.Bull.(2018)41:546-554)、LRKLRKRLLR(SEQ ID NO:48;McCully et al,Curr.Pharm.Design(2018)24(13):1366-1376)、CGHKAKGPRKGKRK(SEQ ID NO:49;McCully et al.(2018))、FKESWREARGTRIERG(SEQID NO:50;McCully et al,(2018))、KSVRTWNEIIPSKGCLR(SEQ ID:51;McCully et al,(2018))、HAIYPRH(SEQ ID NO:52;McCully et al,(2018))、TGNYKALHPHNG(SEQ ID NO:53;McCully et al,(2018))、THRPPMWSPVWP(SEQ ID NO:54;McCully et al,(2018))、及YTIWMPENPRPGTPCDIFTNSRGKRASNG(SEQ ID NO:55;美国第2018/0028677号专利公开)。其他BBB进入胜肽于美国第2011/0230416、2012/0141416、及2013/0108548号专利公开中描述。
在部分实施方案中,该多部分胜肽可连接至免疫球蛋白Fc区。该Fc区可增强稳定性及体内的半衰期,以及可有助于募集携有Fc受体的自然杀手细胞、巨噬细胞、嗜中性球、及肥大细胞,这些细胞可刺激吞噬或细胞毒性以通过抗体介导的吞噬作用或抗体依赖性细胞介导的胞毒作用来破坏微生物或受感染的细胞。当使用衍生自抗体的标靶用剂或Fc区时,这些区域较佳使用本领域技术人员熟知方法进行“人源化”。
于表现载体中编码的多部分胜肽可进一步包括剪切识别序列,以用于蛋白水解或内肽酶剪切序列。内肽酶剪切识别序列的引入可促进真核或哺乳动物细胞中存在的合适内肽酶进行位点特异性剪切,该内肽酶为例如天冬酰胺内肽酶、因子Xa、弗林蛋白酶(furin)、凝血酶、组织蛋白酶B、纤溶酶及各种基质金属蛋白酶(MMP),例如MMP2、MMP7、MMP9或MMP14。
在某些实施方案中,合适的内肽酶剪切识别序列的放置可用于释放与胜肽连接的脂质体部分及/或连接的PEG部分,或者用于使一个或多个胜肽区域彼此释放,使得一个或多个这些胜肽区域可在例如其标靶位点处彼此独立地作用。
天冬酰胺内肽酶(也称为豆荚蛋白(legumain))是溶酶体半胱胺酸蛋白酶,其剪切天冬酰胺的C-端侧上的蛋白质底物,例如Asn-Asp或Asn-Xaa-Asn。在某些实施方案中,该多部分抗癌胜肽包括通过天冬酰胺内肽酶剪切序列(NXN(PEG-NAN-SMR-CLU))化学共价至SMR胜肽的PEG部分(例如10Kd)。通过NXN序列共价至PEG的例示性胜肽包括NXNVGFPVAAVGFPV(SEQ ID NO:36)及NXNVGFPVAAVGFPVHPLSKHPYWSQP(SEQ ID NO:37)。
MMP2、MMP7、MMP9或MMP14可剪切的序列包括PLGLAG、PLG-C(me)-AG、RPLALWRS(SEQID NO:21)、ESPAYYTA(SEQ ID NO:22)、DPRSFL(SEQ ID NO:23)、PPRSFL(SEQ ID NO:24)、RLQLKL(SEQ ID NO:25)、及RLQLK(Ac)(SEQ ID NO:26)。组织蛋白酶B是肿瘤相关蛋白酶,其可用于二胜肽序列缬胺酸-瓜胺酸及Phe-Lys。弗林蛋白酶剪切识别序列Arg-X-X-Arg(SEQID NO:27),更佳为Arg-X-(Lys/Arg)-Arg(SEQ ID NO:28)。因子Xa在精胺酸残基之后在其较佳的剪切位点中剪切Ile-(Glu或Asp)-Gly-Arg(SEQ ID NO:29),并有时在其他碱性残基处剪切。此取决于蛋白质底物的构象。在已定序者中,最常见的二级位点为Gly-Arg。凝血酶较佳在例如序列LVPRGS(SEQ ID NO:30)中的Arg级Gly残基之间剪切。
本说明书的多部分胜肽可为化学修饰的,其使用一个或多个包括但不限于以下的方法:酰胺化、乙酰化(包括N端乙酰化)、羧化、糖基化、甲基化(例如使用甲基进行的α-氢取代)、羰基化、磷酸化、聚乙二醇化、二聚化、链间及/或链内二硫键的添加、反式烯烃的添加、利用已知保护基团/封闭基团进行的衍生化、环化、D-胺基酸取代、与抗体分子的连接或其他细胞配体等的连接。
本说明书的多部分胜肽可经修饰以含有其他非蛋白质性质的部分,该部分为本领域已知且容易获得。较佳地,适于蛋白质衍生化的部分为水溶性聚合物。水溶性聚合物的非限制性例子包括但不限于,聚乙二醇(PEG)、聚乙烯醇(PVA)、乙二醇/丙二醇共聚物、羧甲基纤维素、葡聚糖、聚乙烯醇、聚乙烯吡咯烷酮、聚-1,3-二氧戊环、聚-1,3,6-三恶烷、乙烯/顺丁烯二酸酐共聚物、聚胺基酸(均聚物或无规共聚物)、及葡聚糖或聚(N-乙烯基吡咯烷酮)聚乙二醇、丙二醇(PPG)均聚物、聚丙烯氧化物/氧化乙烯共聚物、聚氧乙烯化的多元醇(例如甘油、POG)、聚乙烯醇及其混合物。聚乙二醇丙醛因其在水中的稳定性而于制造中具有优势。
其他修饰包括例如点突变、插入、缺失、截短及骨架取代,例如NH至NCH3。此外,可通过插入一个或多个D胺基酸来修饰胜肽。而且,可使用脯胺酸残基环大小由5元环变为4、6或7元环的脯胺酸类似物。环状基团可为饱和或不饱和的,且若为非饱和的,则可为芳族或非芳族。
该多部分胜肽可包括修饰,其包括在该胜肽的N端终端、该胜肽的C端终端或二者处引入本文所述的任何功能区域。替代地或另外地,N端终端的修饰可包括C端终端的乙酰化(Ac)残基及/或酰胺化(NH2)残基。当C端终端被酰胺化时,胺基酸的羧酸被转化为酰胺,即,NH2-CH2-C(O)-NH2。
该多部分胜肽可进一步含有一个或多个共价连接的官能基团,较佳地连接到该多胜肽的N端及C端的任一个或两个上。这些共价连接基团可包括稳定剂、偶联剂、配体、酶底物及/或前述的组合。较佳的基团包括N端的酰基及C端的半胱胺(cya)偶联基团。对后者可方便地连接其他化学部分,例如染料、配体、小分子药物、蛋白质、酶、酶底物等。半胱胺(cya)的替代物也为本领域技术人员已知。为了稳定及/或阻断例如可用烷基(如甲基或乙基)代替cya,已知该烷基可方便地定位于-COOH基团上。
N端修饰还可包括但不限于,甲基化(即,-NHCH3或-NH(CH3)2)、加入1-胺基-环己烷-羧酸部分(Chex);加入羧苯甲酰基(carbobenzoyl)、或用含有RCOO-限定的羧酸官能基团的任何封闭基团封闭胺基终端,其中R选自由萘基、吖啶基、甾基及类似基团组成的群组。
衍生基团包括但不限于,含巯基的基团或部分,其可位于多部分胜肽的C端,即使其不与另一个化学部分偶联。在一实施方案中,C端可用半胱胺酸基团(-NH-CH2-CH2-SH)修饰,其可允许进一步与药物偶联。半胱胺基团与使用Fmoc策略的胜肽合成兼容,并产生C端保护的胜肽。或者,该胜肽可包括含有巯基(-SH)基团的C端半胱胺酸残基,该巯基可任选地用于其他部分偶联。在另一实施方案中,C端包括2,4-二胺基-丁酸(DAB)部分。C端修饰可进一步包括用羧酰胺基基团取代游离酸或在羧基终端形成环状内酰胺以引入结构限制。
20个遗传编码的胺基酸(或D-胺基酸)的天然存在侧链可经具有相似性质的其他侧链替换,例如具有如烷基、低级烷基、环状4-、5-、6-至7-元环烷基、酰胺、酰胺低级烷基、酰胺二(低级烷基)、低级烷氧基、羟基、羧基及其低级酯衍生物、以及4-、5-、6-至7-元杂环。
这些取代可包括但不限于:(1)非标准带正电荷的胺基酸,例如鸟胺酸、N-(4-胺基丁基)-甘胺酸,其赖胺酸侧链与“N端”连接且胺基丙基或胺基乙基与甘胺酸的胺基连接;(2)非天然存在的胺基酸,其无净电荷,侧链类似于精胺酸,例如瓜胺酸,其带有或不带有亚甲基;(3)具有OH的非标准非天然存在的胺基酸(例如丝胺酸),例如高丝胺酸、羟脯胺酸、羟基缬胺酸及青霉胺;(4)脯胺酸衍生物,例如D-Pro,包括3,4-脱氢脯胺酸、焦谷胺酰胺、在环上带有氟取代的脯胺酸、1,3-噻唑烷-4-羧酸;(5)组胺酸衍生物,例如β-(2-噻吩基)-丙胺酸;或者,(6)烷基衍生物,例如2-胺基丁酸、正缬胺酸、正亮胺酸、高亮胺酸及α-胺基异丁酸。
在其他实施方案中,可通过分别以N端胺基分别对羧基或酯的-OH或酯基(-OR)进行内部取代以诱导C端羧基或C端酯基环化形成环肽。举例言之,在合成及剪切获得肽酸后,通过合适的羧基活化剂如在溶液(例如在二氯甲烷(CH2Cl2)、二甲基甲酰胺(DMF)混合物中)的二环已基碳二亚胺(DCC)将游离酸转化成活化的酯。而后通过以N端胺对活化酯进行内部取代形成环肽。通过使用非常稀的溶液可增强内部环化,此与聚合相反。这些方法在本领域周知。
在其他实施方案中,本说明书的多部分胜肽经环化或在胜肽终端包括脱胺基或脱羧基残基,使得不存在终端胺基或羧基。此可降低蛋白酶的易感性及/或限制胜肽的构象。本说明书的化合物的C端官能基团包括酰胺、酰胺低级烷基、酰胺二(低级烷基)、低级烷氧基、羟基及羧基及其低级衍生物、以及其医药上可接受的盐。该多部分胜肽可通过添加N端及/或C端半胱胺酸进行环化且通过二硫键或其他侧链相互作用环化该胜肽。
在较佳的实施方案中,该多部分胜肽(或其医药组成物)具有结构A-B-C-D/E,其中A为PEG,例如10kD的PEG;B为用于内肽酶的胜肽剪切连接子序列,例如天冬酰胺内肽酶;C为含有SMR的胜肽序列,例如VGFPVAAVGFPV(SEQ ID NO:2);D为Clu-BP胜肽序列,例如HPLSKHPYWSQP(SEQ ID NO:3);以及,E为细胞穿透胜肽(CPP)序列,例如GRKKRRQRRRPPQ(SEQID NO:38)。
本说明书的多部分胜肽可作为具有或不具有PEG部分的裸肽投予,或者其可引入合适的载剂之中、之上或与之结合,该载剂为例如脂质体、奈米颗粒、水凝胶、微胶囊、病毒或嗜菌体或病毒样颗粒(VLP)。
例示性的奈米颗粒包括顺磁性奈米颗粒、超顺磁性奈米颗粒、金属奈米颗粒、聚合物奈米颗粒、奈米蜗杆(nanoworm)、奈米乳液、奈米凝胶、富勒烯样材料、无机奈米管、树枝状聚合物(例如带有共价连接的金属螯合物)、奈米胶囊、奈米球、奈米纤维、奈米角(nanohom)、奈米-洋葱、奈米棒、奈米绳及量子点。奈米粒子可产生可检测信号,举例言之,通过吸收及/或发射光子(包括射频及可见光子)及电浆子共振。奈米颗粒可以为可生物降解的或不可生物降解的。
在某些实施方案中,奈米颗粒为金属奈米颗粒、金属氧化物奈米颗粒、或半导体奈米晶体。该金属奈米颗粒或金属氧化物奈米颗粒的金属可包括钛、锆、铪、钒、铌、钽、铬、钼、钨、锰、鎝、铼、铁、钌、锇、钴、铑、铱、镍、钯、铂、铜、银、金、锌、镉、钪、钇、镧、镧系元素或锕系元素(例如铈、镨、钕、巨、钐、铕、钆、铽、镝、钬、铒、铥、镱、镏、钍、镤、及铀)、硼、铝、镓、铟、铊、硅、锗、锡、铅、锑、铋、钋、镁、钙、锶及钡。在某些实施方案中,该金属可为铁、钌、钴、铑、镍、钯、铂、银、金、铈或钐。该金属氧化物可为任何这些原料或原料组合的氧化物。举例言之,该金属可为金、或该金属氧化物可为氧化铁、氧化钴、氧化锌、氧化铈及氧化钛。金属及金属氧化物奈米颗粒的制备描述于例如美国第5,897,945及6,759,199号专利中。
在其他实施方案中,聚合物奈米颗粒由生物可降解聚合物、天然生物可降解聚合物或前述的组合进行制造。合成生物可降解聚合物可包括聚酯,例如聚(乳酸-乙二醇共聚物)(PLGA)及聚己内酯;聚原酸酯、聚酸酐、聚二恶烷、聚氰基丙烯酸烷基酯(PAC)、聚草酸酯、聚亚氨基碳酸酯、聚氨酯、聚磷腈、或前述的组合。天然生物可降解聚合物可包括淀粉、透明质酸、肝素、明胶、白蛋白、几丁聚糖、葡聚糖、或前述的组合。
在某些实施方案中,上述载剂(包括奈米颗粒)可连接至本文所述的CPP胜肽、标靶胜肽、粒线体标靶胜肽、及/或BBB进入胜肽,以促进本文所述的活性剂的载体介导递送。
胜肽编码多核苷酸
本说明书的另一方面关于编码本文所述的任何多部分胜肽的多核苷酸。在一实施方案中,该多核苷酸为表达载体。如本文使用,术语“表达载体”指包括编码本说明书的多部分胜肽的多核苷酸的非病毒载体或病毒载体,其中胜肽编码序列可操控地连接至足以在细胞中表达该胜肽的调节序列。一种类型的非病毒载体为“质体(plasmid)”,其包括环状双链DNA环,在该DNA环内可连接其他的DNA区段。在本说明书中,“质体”及“载体”可互换使用,因为质体是最常使用的载体形式。
可基于待用于表达的宿主细胞来选择调节序列,使设计表达载体及包括调节序列取决于如待转化宿主细胞的选择、所欲蛋白质的表达水平、胜肽是否分泌至细胞外环境等因素。可将本发明的表达载体引入宿主细胞中,以指导本说明书的多部分胜肽在体外为生产目的的表达、或在体内为治疗目的的表达。
如本文使用,术语“对照序列”或“调节序列”指在特定宿主生物中表达可操控地连接的编码序列所需DNA序列。术语“对照/调节序列”旨在包括启动子、增强子及其他表达控制元件(例如多腺苷酸化信号)。对照/调节序列包括在许多类型的宿主细胞中指导核苷酸序列的组成型表达的这些序列,以及仅在某些宿主细胞中指导核苷酸序列表达的这些序列(例如组织特异性调节序列)。
当核酸序列与另一核酸序列处于功能关系时,前者与后者彼此为“可操控地连接”。举例言之,在某些实施方案中,表达载体编码前序列或信号胜肽,其与胜肽编码序列可操控地连接,用于表达参与该多胜肽分泌的前蛋白。此外,若启动子或增强子影响序列的转录,则认为启动子或增强子与编码序列可操控地连接,且若核糖体结合位点被定位以便于转译,则其与编码序列可操控地连接。一般而言,“可操控地连接”指被连接的DNA序列为连续的,并且在分泌前导的情况下,是连续的并且处于阅读阶段。然而,增强子不需为连续的。连接这些序列可通过在方便的限制性位点连接或通过使用合成的寡核苷酸衔接子(adaptor)、引子及/或连接子根据本领域常规操作来完成。
在某些情况中,可通过使用病毒载体固有的或工程化到该病毒载体中的标靶特征,将这些载体工程化以标靶某些疾病或细胞群。特异性细胞可对于多核苷酸的递送及表达被“标靶”。因此,在此情况下,术语“标靶”可基于以用于递送至特定细胞的抗体、衣壳或包膜蛋白的形式的内源或异源结合剂的使用、用于将表达限制于特定细胞亚群的组织特异性调控元件的使用、或前述二者。
在某些实施方案中,表达载体经工程改造以指导胜肽于特定细胞类型中普遍或较佳地表达(例如组织特异性调控元件被用于表达多核苷酸)。因此,在某些实施方案中,胜肽的表达处于组织特异性或普遍存在的启动子(例如CMV启动子或CMV-鸡β-肌动蛋白杂合体(CAG)启动子)的控制下。在其他实施方案中,可使用组织特异性或肿瘤特异性启动子。例示性的组织特异性调控元件为本领域已知,且可包括肝特异性启动子(例如白蛋白启动子)、淋巴特异性启动子、上皮细胞特异性启动子、T细胞受体及免疫球蛋白的启动子、神经元特异性启动子(例如神经细丝启动子)、胰腺特异性启动子(例如胰岛素启动子)及乳腺特异性启动子(例如奶乳清启动子)。还包括发育调节的启动子(例如α-胎蛋白启动子)。
在某些实施方案中,多部分表现构建体可与粒线体标靶胜肽或前导序列连接,以促进表达构建体进入粒线体细胞中,如美国第20040192627号专利公开所述。常规方案可用于将表达构建体与粒线体标靶胜肽偶联,例如pGeneGripTM技术(Genlantis/Gene TherapySystems,Inc.,San Diego,CA)。替代地,多部分胜肽编码序列可融合至粒线体标靶序列,以如上述指导表达的胜肽易位至粒腺体中。
在其他实施方案中,多部分胜肽编码序列可与粒线体穿透部分或如上述的粒线体标靶信号序列融合。作为粒线体穿透部分的例示性核酸(如在美国第5,569,754号专利所述的)包括例如CCGCCAAGAAGCG(SEQ ID NO:31)、GCGTGCACACGCGCGTAGACTTCCCCCGCAAGTCACTCGTTAGCCCGCCAAGAAGCGACCCCTCC GGGGCGAGCTGAGCGGCGTGGCGCGGGGGCGTCAT(SEQ ID NO:32)、ACGTGCATACGCACGTAGACATTCCCCGCTTCCCACTCCAAAGTCCGCCAAGAAGCGTATCCCGC TGAGCGGCGTGGCGCGGGGGCGTCATCCGTCAGCTC(SEQ ID NO:33)或ACTTCCCCCGCAAGTCACTCGTTAGCCCGCCAAGAAGCGACCCCTCCGGGGCGAGC TG(SEQ ID NO:34)。
在部分实施方案中,多部分胜肽编码序列可与信号胜肽区域融合,用于自表达胜肽的细胞分泌该胜肽。当成熟胜肽自细胞分泌时,自成熟胜肽中除去信号胜肽序列。由于给定的信号胜肽序列可影响胜肽表达水平,因此胜肽编码多核苷酸可包括本领域已知的多种不同N端信号胜肽序列中的任何一种。
在部分实施方案中,表达载体为病毒载体。病毒载体可来自于腺相关病毒(AAV)、腺病毒、疱疹病毒、牛痘病毒、脊随灰质炎病毒、痘病毒、逆转录病毒(包括慢病毒如HIV-1及HIV-2)、辛得比斯及其他RNA病毒、α病毒、星状病毒、冠状病毒、正黏液病毒、乳多泡病毒、副黏液病毒、细小病毒、小核糖核酸病毒、披膜病毒等。非病毒载体简单地为“裸露的”表达载体,其不与病毒衍生的组分(例如衣壳及/或包膜)一起包装。
通过直接注射裸DNA或通过将多部分胜肽编码多核苷酸包封在脂质体、奈米颗粒、水凝胶、微胶囊或病毒样颗粒中,非病毒表达载体可用于非病毒基因转移。此类组成物可通过化学偶联进一步连接至标靶区域,以促进核酸标靶递送及/或进入所欲目标细胞。此外,质体载体可与合成的基因转移分子(例如聚合DNA结合阳离子如聚赖胺酸、鱼精蛋白及白蛋白)一起培养,并连接至细胞标靶配体,例如脱唾液酸血清类黏蛋白(asialoorosomucoid)、胰岛素、半乳糖、乳糖或转铁蛋白。
替代地,可使用裸DNA。通过压实或使用可生物降解的乳胶珠可改善裸DNA的摄取效率。通过处理珠子以增加疏水性进而促进胞内体破坏及DNA释放至细胞质,可进一步改善此递送。
医药组成物
在部分实施方案中,医药组成物包括多部分胜肽,该胜肽包括至少一个来自HIV-1Nef的SMR胜肽、至少一个凝聚素(Clu)结合蛋白(Clu-BP)及医药上可接受载剂。此外,该多部分胜肽可包括任何上述修饰。
在另一实施方案中,医药组成物包括编码多部分胜肽的表达载体,该胜肽包括至少一个来自HIV-1Nef的SMR胜肽、至少一个凝聚素(Clu)结合蛋白(Clu-BP)及医药上可接受载剂,进而该编码胜肽经设计以包括任何上述修饰。
如本文使用,术语“医药上可接受”指当酌情投予至动物或人时,不会产生不利的、过敏的或其他不良反应的分子实体或组成物。如本文使用,术语“医药上可接受载剂”包括任何及全部与药物投予兼容的溶剂、增溶剂、稳定剂、界面活性剂、黏合剂、吸收剂、碱、缓冲剂、赋形剂、润滑剂、控释载剂、稀释剂、乳化剂、保湿剂、润滑剂、凝胶、分散介质、涂层、抗细菌或抗真菌剂、等渗及吸收延迟剂等。这些载剂及试剂用于药物活性物质的用途为本领域所熟知。参见例如:A.H.Kibbe Handbook of Pharmaceutical Excipients,3rded.Pharmaceutical Press,London,UK(2000)。
例示性的载剂或赋形剂包括但不限于,碳酸钙、磷酸钙、各种糖、淀粉、纤维素衍生物、明胶、聚合物如聚乙二醇、水、盐水、等渗水溶液、磷酸盐缓冲盐水、右旋糖、0.3%甘胺酸水溶液、甘油、乙醇等、以及前述的组合。在许多情况下,较佳地在组成物中包括等渗剂,例如糖、多元醇如甘露醇、山梨糖醇、或氯化钠、或者用于增强稳定性的糖蛋白(例如白蛋白、脂蛋白及球蛋白)。医药上可接受载剂可进一步包括少量辅助物质,例如湿润剂或乳化剂、防腐剂或缓冲剂。这些试剂增强治疗剂的保质期或有效性。在某些实施方案中,医药上可接受载剂包括血清白蛋白。
可改变的制剂特征包括例如pH及渗透压。举例言之,可能希望获得具有与人血液或组织相似的pH及渗透压的制剂,以在肠胃外投予时促进制剂的有效性。
缓冲剂可用于本发明,除了其他目的外,还用于操纵药物制剂的总pH(特别是胃肠外使用所欲pH)的目的。本领域已知的各种缓冲剂可用于本发明制剂中,例如有机或无机酸、碱或胺基酸的各种盐,并包括各种形式的柠檬酸盐、磷酸盐、酒石酸盐、琥珀酸盐、己二酸盐、顺丁烯二酸盐、乳酸盐、乙酸盐、碳酸氢盐或碳酸盐离子。用于本发明中的本说明书的组成物的肠胃外投予形式特别有利的缓冲剂包括磷酸钠、磷酸钾、琥珀酸钠、及柠檬酸钠。
氯化钠可用于在0-300mM的浓度改变溶液的张力(对于液体剂型,最佳为150mM)。可包括冷冻保护剂以用于冻干剂型,主要是0-10%蔗糖(最佳为0.5-1.0%)。其他合适的冷冻保护剂包括海藻糖及乳糖。可包括用于冻干剂型的填充剂,主要是1-10%甘露醇(最佳为2-4%)。稳定剂可于液体及冻干剂型使用,主要是1-50mM的L-甲硫胺酸(最佳为5-10mM)。其他合适的填充剂包括甘胺酸、精胺酸,其可包括0-0.05%聚山梨醇酯-80(最佳为0.005-0.01%)。
在一实施方案中,磷酸钠以接近20mM的浓度使用,以达到约7.0的pH。特别有效的磷酸钠缓冲体包括磷酸二氢钠一水合物及磷酸氢二钠七水合物。当使用此磷酸钠一元碱及磷酸钠二元碱的组合时,各自的有利浓度为约0.5至约1.5mg/ml一元碱及约2.0至约4.0mg/ml二元碱,较佳浓度为约0.9mg/ml一元碱及约3.4mg/ml的磷酸二元碱。制剂的pH根据使用的缓冲剂的量来变化。
取决于剂型及预期的投予途径,可替代地使用不同浓度的缓冲剂或使用其他添加剂来调节组成物的pH以包括其他范围是有利的。本发明的组成物的有用pH范围包括约2.0的pH至约12.0的pH。
在部分实施方案中,在本发明公开的制剂中使用界面活性剂也是有利的,其中这些界面活性剂不会破坏所使用的药物递送系统。证明了有用的界面活性剂或抗吸附剂包括聚氧乙烯山梨糖醇、聚氧乙烯山梨糖醇酐单月桂酸酯、聚山梨醇酯-20如Tween-20TM、聚山梨醇酯-80、聚山梨醇酯-20、羟基纤维素、偕胺醇(genapol)及BRIJ界面活性剂。举例言之,当在本发明中使用任何界面活性剂来制备可肠胃外投予的组成物时,以约0.01至约0.5mg/ml的浓度使用该组成物是有利的。
根据组成物及配方设计的特定需要或预期用途,本领域技术人员容易确定其他有用的添加剂。一种这样特别有用的额外物质为氯化钠,其可用于调节制剂的渗透压以获得所欲渗透压。用于肠胃外投予的所公开组合物的最佳渗透压约为270至330mOsm/kg。用于肠胃外投予特别是可注射的组成物的最佳渗透压约为300mOsm/kg,可通过使用浓度为约6.5至7.5mg/ml的氯化钠达成,氯化钠浓度为约7.0mg/ml是特别有效的。
多部分胜肽可在无菌条件下做为冻干粉末储存,并在投予前与无菌水溶液混合。如上述,用于重新悬浮的胜肽水溶液可含有接近物理条件所需的医药上可接受的辅助物质,例如如上所述的pH调节剂及缓冲剂及张力调节剂等。或者,多部分胜肽可在投予前作为悬浮液储存,较佳作为水悬液储存。
在某些较佳的实施方案中,医药组成物中的多部分胜肽为聚乙二醇化的。聚乙二醇化(PEG化)是将聚乙二醇聚合物链共价连接到另一分子(通常是药物或治疗性胜肽/蛋白质)的过程。PEG化可通过将PEG的反应性衍生物与多部分胜肽一起培养来完成。PEG与多部分胜肽的共价连接可以“掩盖”宿主系统中的多部分胜肽(降低的免疫源性及抗原性),增加多部分胜肽的流体动力学尺寸(溶液中的尺寸),通过减少肾清除来延长期循环时间。PEG化还可以为疏水蛋白提供水溶性。
PEG分子通常表征为具有例如约2至约1000、或约2至约300个重复单元。举例言之,水溶性聚合物包括但不限于,PEG、聚(环氧乙烷)(PEO)、聚环氧乙烷(POE)、聚乙烯醇、羟乙基纤维素或葡聚糖,通常偶联至蛋白质以增加蛋白质的稳定性或尺寸等,如美国第2012/0171115号专利公开中所述。
PEG、PEO及POE为环氧乙烷的低聚物或聚合物。在PEG的情况下,这些低聚物或聚合物通过例如环氧化物环上的氢氧根离子的亲核攻击引发的环氧乙烷阴离子开环聚合来制备。用于蛋白质修饰的更有效的PEG形式之一为单甲氧基PEG(mPEG)。
较佳的PEG为单分散的或多分散的,较佳为单分散的。技术人员将认识到PEG可为多分散或单分散的。多分散PEG包括具有不同分子量的PEG混合物。在多分散PEG的情形下,提及特定分子量将被理解为指混合物中PEG的数均分子量。尺寸分布在统计学上通过其重均分子量(MW)及其数均分子量(Mn)表征,其比率称为多分散指数(MW/Mn)。在某些方面,通过质谱法测量MW及Mn。大多数PEG-蛋白质偶联物(特别是偶联至大于1KD的PEG的偶联物),由于母体PEG分子的30多分散性质表现出一系列分子量。例如,在mPEG2K(Sunbright ME-020HS,NOF)的情形下,实际分子量分布在1.5-3.0KD的范围内,多分散指数为1.036。基于前述内容,本领域技术人员将理解单分散PEG包括具有基本相同的分子量的PEG混合物。单分散PEG可商购获得,例如购自挪威的Polypure AS。
PEG的平均或较佳分子量可为500Da至200kDa、1至100kDa、2至50kDa、5至25kDa、或5kDa至10kDa,其包括包括在这些范围内的任何整数。
PEG衍生物的合适官能基团的选择基于将与PEG偶联的分子上可用的反应性基团的类型。对于胜肽或蛋白质,典型的反应性胺基酸包括赖胺酸、半胱胺酸、组胺酸、精胺酸、天冬胺酸、谷胺酸、丝胺酸、苏胺酸、酪胺酸。N端胺基及C端羧酸也可通过与醛官能聚合物偶联而用作位点特异性位点。
在某些实施方案中,PEG衍生物通过使PEG聚合物与可与羟基反应的基团(通常为酸酐、酰氯、氯甲酸酯及碳酸酯)反应来制备。在其他实施方案中,更有效的官能基团(如醛、酯、酰胺等)可用于蛋白质偶联。
在某些实施方案中,异双功能PEG用于偶联。这些异双功能PEG可用于连接两个实体,其中需要亲水的、挠性的与生物兼容的间隔物。异双功能PEG的较佳的端基为顺丁烯二酰亚胺、乙烯基砜、吡啶基二硫化物、胺、羧酸及NHS酯。在其他实施方案中,聚乙二醇化试剂含有支化的Y型或梳型聚合物,该聚合物显示出降低的黏度及缺少器官累积。
如美国第2012/0171115号专利公开所述,本领域已知多种用于将PEG偶联至胜肽或蛋白质的方法。PEG的偶联可包括使用可剪切或不可剪切的间隔物部分。在部分实施方案中,可剪切的间隔物部分为氧化还原可剪切的间隔物部分,使得间隔物部分在具有较低氧化还原电位的环境中是可剪切的,例如细胞质及具有较高浓度的具有游离巯基分子的其他区域。可能由于氧化还原电位的变化而被剪切的间隔物部分的例子包括含有二硫化物的这些物质。可在偶联蛋白进入至细胞内时提供剪切刺激,其中细胞质较低的氧化还原电位促进间隔物部分剪切。在PEG的情形下,可活化分子以促进其与胺或咪唑、羧基、羟基或巯基结合。
在另一例子中,pH的降低引起间隔物剪切,进而将化合物释放至标靶细胞中。pH的降低关于许多生理及病理过程,例如胞内体运输、肿瘤生长、炎症及心肌缺血。pH在内体中从生理学上的7.4降至5-6、或在溶酶体中降至4-5。可用于标靶癌细胞的溶酶体或胞内体的酸敏感间隔物部分的例子包括具有酸可剪切的这些物质,例如在缩醛、缩酮、原酸酯、腙、三苯甲基、顺式-乌头基(cis-aconityl)或硫代胺基甲酰基中发现的(参见例如美国第4,569,789、4,631,190、5,306,809及5,665,358号专利)。其他例示性的酸敏感性间隔物部分包括二胜肽序列Phe-Lys及Val-Lys。
可剪切的间隔物部分可对与特定标靶细胞相关的生物学供应的剪切剂敏感,例如溶酶体或肿瘤相关酶。可使用酶促进剪切的连接部分的例子包括但不限于酯及内肽酶剪切识别位点。
活化的PEG可与氰尿酰氯一起使用,以产生PEG二氯三嗪衍生物。该衍生物可与多种功能性亲核官能基团反应,例如赖胺酸、丝胺酸、酪胺酸、半胱胺酸及组胺酸。用于与蛋白质偶联的两种广泛使用的PEG形式为琥珀酰亚胺基碳酸酯PEG及苯并三唑碳酸酯PEG(BTC-PEG;美国第5,560,234号专利)。此两种化合物皆优先与赖胺酸残基反应形成胺基甲酸酯键,但已知其也与组胺酸及酪胺酸反应。SC-PEG比BTC-PEG稍微更耐水解。
可用于偶联蛋白质的另一种PEG为PEG-丙醛(美国第5,252,714号专利)。该化学物的一个优点为在酸性条件下(约pH5),其对N端α-胺具有很大的选择性,进而避免了非特异性偶联的潜在问题。PEG-丙醛的缩醛衍生物(即,PEG-乙醛)提供了额外的益处,因为其提供比PEG-丙醛更长的储存(美国第5,990,237号专利)。
PEG羧酸的活性酯可能为最常用的蛋白质偶联酰化剂之一。活性酯在接近生理条件下与一级胺反应形成稳定的酰胺。通过使PEG-羧酸与N-羟基琥珀酰亚胺(NHS或HOSu)及碳二亚胺反应,使得PEG-羧酸活化成琥珀酰亚胺基活性酯。PEG的例示性羧酸衍生物包括羧甲基化PEG(CM-PEG)、丁酸衍生物及丙酸衍生物(美国第5,672,662号专利)。通过添加亚甲基单元改变活性酯及PEG主链的间的距离可显著影响对水及胺的反应性(例如通过减少水解)。替代地或另外地,通过将α-支化部分引入羧酸可降低水解。
蛋白质中游离半胱胺酸残基的PEG化可用于位点特异性偶联(例如使用经修饰以包括如本文所述的半胱胺酸残基的蛋白质)。用于半胱胺酸偶联的例示性PEG衍生物包括PEG-顺丁烯二酰亚胺、PEG-乙烯基砜、PEG-碘乙酰胺及PEG-邻吡啶基二硫化物。用于将PEG偶联至半胱胺酸残基及使用PEG-乙烯基砜偶联的例示性方法为本领域周知。
美国第5,985,263号专利描述了将PEG偶联至组胺酸的二级胺基团的方法,其具有比一级胺更低的pKa。该方法的一个优点为酰基-组胺酸键不稳定,此意味着胜肽或蛋白质被缓慢释放(即,偶联物表现为缓释剂或前驱药物)。
PGE化的另一方法为利用N端丝胺酸或苏胺酸,其可如上述转化为高碘酸盐。使用此方法,PEG已与生物活性蛋白偶联(例如Gaertner and Offord,1996)。PEG也可与糖类基团偶联。
配制本说明书的医药组成物以与其预期的投予途径兼容。投予途径的例子包括肠胃外,例如鞘内、动脉内、静脉内、皮内、皮下、口服、经皮(局部)及经黏膜投予。用于肠胃外、皮内或皮下应用的溶液或悬浮液可包括以下组分:无菌稀释液,例如注射用水、盐溶液、固定油、聚乙二醇、甘油等、丙二醇或其他合成溶剂;抗菌试剂,例如苯甲醇或对羟基苯甲酸甲酯;抗氧化剂,例如抗坏血酸或硫酸氢钠;螯合剂,例如乙二胺四乙酸;缓冲剂,例如乙酸盐、柠檬酸盐或磷酸盐;以及,调节渗透压的试剂,例如氯化钠或葡萄糖。可用酸或碱调节pH,例如盐酸或氢氧化钠。肠胃外制剂可封装在安瓶、一次性注射器、或由玻璃或塑料制成的多剂量小瓶中。
适于注射使用的医药组成物包括无菌水溶液(水溶性的)或分散体及用于临时制备无菌可注射溶液或分散体的无菌粉末。对于静脉内投予,合适的载剂包括生理食盐水、抑菌水、CREMOPHOR ELTM(BASF,Parsippany,NJ)、或磷酸盐缓冲液(PBS)。在全部的情况下,可注射组成物应为无菌且应是达到易于注射程度的流体。其在制造及储存条件下必须是稳定的,且必须防止微生物(例如细菌及真菌)的污染作用。载剂可为溶剂或分散介质,其含有例如水、乙醇、多元醇(例如甘油、丙二醇、及液态聚乙二醇等)、以及前述的合适的混合物。举例言之,通过使用如卵磷脂的涂层,在分散的情况下保持所欲颗粒尺寸及使用界面活性剂,可保持适当的流动性。通过各种抗菌剂及抗真菌剂(例如对羟基苯甲酸酯、氯丁醇、苯酚、抗坏血酸、硫柳汞等)可防止微生物的作用。在许多情况下,较佳地在组成物中包括等渗剂,例如糖、多元醇如甘露醇、山梨糖醇及氯化钠。通过在组成物中包括延迟吸收的试剂(例如单硬脂酸铝及明胶)可达成可注射组成物的延长吸收。
无菌可注射溶液可通过将所需量的多部分胜肽与上列成分中的一种或成分组合(根据需要)加入适当的溶液中,然后过滤灭菌来制备。一般而言,通过将多部分胜肽加入无菌载剂中来制备分散体,该无菌载剂含有基础分散介质及来自上列这些其他所需成分。在用于制备无菌可注射溶液的无菌粉末的情况下,较佳的制备方法为真空干燥及冷冻干燥,其获得活性胜肽加上来自其先前无菌过滤溶液的任何其他所需成分的粉末。
口服组成物通常包括惰性稀释剂或可食用载剂。其可封装在明胶胶囊中或压制成片剂。片剂、丸剂、胶囊剂、锭剂等可含有以下任何成分或具有类似性质的化合物,包括:黏合剂,例如微晶纤维素、黄蓍胶或明胶;赋形剂,例如淀粉或乳糖;崩解剂,例如海藻酸、Primogel或玉米淀粉;润滑剂,例如硬脂酸镁或Stertes;助流剂,例如胶体二氧化硅;甜味剂,例如蔗糖或糖精;或者,调味剂,例如薄荷、水杨酸甲酯或橙子调味剂。
对于通过吸入投予,该胜肽以气溶胶喷雾的形式,自容纳有合适推进剂(例如二氧化碳的气体)的加压容器或分配器或喷雾器递送。
全身投予也可通过经黏膜或经皮方式进行,对于经黏膜或经皮投予,在制剂中使用适合于待渗透屏障的渗透剂。此渗透剂通常是本领域已知的,且包括例如用于经黏膜投予的去污剂、胆盐、及夫西地酸衍生物。经黏膜投予可通过使用鼻喷雾剂或栓剂来达成。对于经皮投予,将医药组成物配制成本领域周知的软膏、油膏、凝胶或乳膏。
在某些实施方案中,配制医药组成物用于控制或延迟释放活性成分。举例言之,在某些实施方案中,该胜肽可与肠溶包衣一起递送,该肠溶包衣作为口服制剂的屏障,以便防止胜肽在抵达小肠之前释放。如本文使用,术语“肠溶包衣”包括一种或多种具有pH依赖性或pH非依赖性释放曲线的聚合物包衣。肠溶包衣丸不溶于胃部酸液(pH约3),但其将溶解在存在于小肠或结肠中的碱性(pH7-9)环境中。肠溶聚合物涂层通常抵抗活性剂的释放,直到在投予后约3-4小时的胃排空滞后期之后的某个时间。
这种肠溶包衣或屏障包衣也用于保护酸不稳定的胜肽,以免暴露于胃酸,将其递送至碱性pH环境(肠道pH5.5及以上),在该环境中其将不会降解并可介导其所需作用。口服制剂可包括多种屏障涂层,该涂层包括多种不同的材料促进以时间方式释放。该涂层可以是糖衣、薄膜包衣(例如基于羟丙基甲基纤维素、甲基纤维素、甲基羟乙基纤维素、羟丙基纤维素、羧甲基纤维素、丙烯酸酯共聚物、聚乙二醇及/或聚乙烯吡喀烷酮)或基于以下物质的涂层:甲基丙烯酸共聚物、邻苯二甲酸醋酸纤维素、羟丙基甲基纤维素邻苯二甲酸酯、羟丙基甲基纤维素乙酸酯琥珀酸酯、邻苯二甲酸聚乙酸乙烯酯、虫胶及/或乙基纤维素。此外,制剂可另外包括延时材料,例如单硬脂酸甘油酯或二硬脂酸甘油酯。
可使用可生物降解、生物兼容的聚合物,例如乙烯乙酸乙烯酯、聚酐、聚乙醇酸、胶原、聚原酸酯及聚乳酸。制备这些制剂的方法对于本领域技术人员而言为显而易见的。该材料也可自例如Alza Corporation and Nova Pharmaceuticals,Inc.商购。脂质体悬浮液(包括用肿瘤抗原或病毒抗原的单株抗体标靶感染细胞的脂质体)也可用作医药上可接受载剂。
将胜肽组成物配制成剂量单位形式对投予便利性及剂量均匀性是特别有利的。合适的单位剂型包括但不限于粉末、片剂、丸剂、胶囊、锭剂、栓剂、贴剂、鼻喷雾剂、注射剂、可植入的缓释制剂、脂质复合物等。
治疗方法
在另一方面,本说明书提供用于治疗癌症及感染性疾病的方法,在部分实施方案中,本申请关于一种用于治疗癌症的方法。该方法包括对有需要的个体投予有效量的医药组成物的步骤,其中该医药组成物包括含有至少一个来自HIV-1Nef的分泌修饰区(SMR)胜肽及至少一个凝聚素(Clu)结合蛋白(Clu-BP)的多部分胜肽。该个体可具有选自由以下组成的群组的癌症:白血病、淋巴瘤、癌、黑色素瘤、肉瘤、生殖细胞肿瘤及胚胎细胞瘤。
如本文使用,术语“白血病”指血液形成器官的进行性恶性疾病,其特征通常在于血液及骨髓中白细胞及其前驱物的不正常增殖及发育。例示性白血病包括例如急性非淋巴细胞白血病、慢性淋巴细胞白血病、急性粒细胞白血病、慢性粒细胞白血病、急性早幼粒细胞白血病、成人T细胞白血病、白血球缺乏性白血病、白细胞增多性白血病、嗜碱性球白血病、胚胎细胞白血病、牛白血病、慢性髓细胞白血病、皮肤白血病、胚胎白血病、嗜酸粒细胞白血病、格罗斯白血病、毛细胞白血病、成血细胞白血病、血干细胞白血病、组织细胞白血病、干细胞白血病、急性单核细胞白血病、白细胞减少症白血病、淋巴细胞性白血病、淋巴母细胞白血病、淋巴球性白血病、成淋巴性白血病、淋巴样白血病、淋巴肉瘤细胞白血病、肥大细胞白血病、巨核细胞白血病、微小细胞白血病、单核细胞白血病、骨髓胚细胞白血病、髓细胞白血病、骨髓性粒细胞白血病、髓单核细胞白血病、内格利白血病、浆细胞白血病、浆球性白血病、前骨髓细胞性白血病、Rieder氏细胞白血病、希林氏性白血病、干细胞白血病、亚白血性白血病及未分化细胞白血病。
术语“淋巴瘤”指由淋巴细胞发展而来的一组血细胞肿瘤。例示性淋巴瘤包括例如霍奇金淋巴瘤(HL)及非霍奇金淋巴瘤。
术语“癌(carcinoma)”指上皮细胞的恶性生长,其倾向于渗入至周围组织并引起转移。例示性的癌包括例如腺泡癌、腺样癌、腺囊性癌、腺样囊性癌、腺瘤(carcinomaadenomatosum)、肾上腺皮质瘤、肺泡癌、肺泡细胞癌、基底细胞癌(basal cellcarcinoma)、基底细胞癌(carcinoma basocellulare)、基底细胞样癌、基底鳞状细胞癌、支气管肺泡癌、支气管癌、支气管肺癌、脑癌、胆管细胞癌、绒毛膜癌、胶体癌、粉刺癌、子宫体癌、筛状癌、铠甲状癌(carcinoma en cuirasse)、癌疮(carcinoma cutaneum)、圆柱形癌、圆柱形细胞癌、导管癌、硬癌、胚胎癌、脑鳞癌、表皮样癌、癌上皮腺样瘤、外生癌、癌前病变、癌纤维、明胶癌、凝胶状癌、巨细胞性癌(giant cell carcinoma)、巨细胞癌(carcinomagigantocellulare)、腺癌、颗粒细胞癌、毛基质癌、多血癌、肝细胞癌、贺氏细胞癌、透明癌、超型态癌(hypemephroid carcinoma)、婴儿胚胎癌、原位癌、表皮内癌、上皮内癌、克氏癌、古氏细胞癌、大细胞癌、透镜状癌(lenticular carcinoma)、透镜状癌(carcinomalenticulare)、脂肪瘤癌、淋巴上皮癌、髓癌、髓样癌、黑色素瘤、软瘤、黏液癌(mucinouscarcinoma)、黏液分泌性癌、黏液细胞癌、黏液表皮样癌、黏液癌(carcinoma mucosum)、黏液癌(mucous carcinoma)、黏液瘤样癌、鼻咽癌、燕麦细胞癌、骨化癌、骨样癌、乳头状癌、门静脉癌、浸润前癌、棘细胞癌、糜烂癌、肾脏的肾细胞癌、储备细胞癌、癌肉瘤、施耐德氏癌、硬化癌、阴囊癌、印戒细胞癌、单纯癌、小细胞癌、类囊体癌、球状细胞癌、梭形细胞癌、海绵母癌、鳞状细胞癌、鳞状细胞癌、线状癌、毛细血管扩张癌、毛细血管扩张性癌、移行细胞癌、结节性皮癌、结节癌、疣状癌及绒毛状癌。
术语“肉瘤”指由例如胚胎结缔组织的物质构成的肿瘤,且通常由嵌入纤维状或均质物质中的紧密堆积的细胞组成。例示性的肉瘤包括例如软骨肉瘤、纤维肉瘤、淋巴肉瘤、黑色肉瘤、黏液肉瘤、骨肉瘤、阿氏肉瘤、脂肉瘤、脂肪肉瘤、肺泡软组织肉瘤、成釉细胞肉瘤、葡萄状肉瘤、绿色肉瘤、绒毛膜癌、胚胎肉瘤、威氏肿瘤肉瘤、子宫内膜肉瘤、间质肉瘤、尤文氏肉瘤、筋膜肉瘤、成纤维肉瘤、巨细胞肉瘤、粒细胞肉瘤、霍奇金肉瘤、特发性多发性色素性出血性肉瘤、B细胞免疫母细胞肉瘤、淋巴瘤(如非霍奇金淋巴瘤)、T细胞免疫母细胞肉瘤、简森氏肉瘤、卡波西氏肉瘤、枯氏细胞肉瘤、血管肉瘤、白细胞肉瘤、恶性间质肉瘤、骨肉瘤、网状肉瘤、劳斯肉瘤、浆细胞肉瘤、滑膜肉瘤及毛细血管肉瘤。
术语“黑色素瘤”指由皮肤及其他器官的黑色素细胞系统产生的肿瘤。黑色素瘤包括例如肢端黑色素瘤、无色素黑色素瘤、良性青少年黑色素瘤、克劳德曼氏黑色素瘤、S91黑色素瘤、哈-帕二氏黑色素瘤、幼年黑色素瘤、扁桃体恶性黑色素瘤、恶性黑色素瘤、结节性黑色素瘤、舌下黑色素瘤、及表面扩散黑色素瘤。
其他癌症包括例如霍奇金病、多发性骨髓瘤、神经母细胞瘤、乳腺癌、卵巢癌、肺癌、横纹肌肉瘤、原发性小血版增多症、原发性巨球蛋白血症、小细胞肺肿瘤、原发性脑肿瘤、胃癌、结肠癌、恶性胰腺软脑膜瘤、恶性类癌、癌前皮肤病变、睪丸癌、甲状腺癌、神经母细胞瘤、食道癌、泌尿生殖道癌、恶性高钙血症、子宫颈癌、子宫内膜癌及肾上腺皮质癌。在一实施方案中,个体罹患乳癌。
在其他实施方案中,本申请关于用于治疗感染性疾病的方法。该方法包括对有需要的个体投予有效量的医药组成物的步骤,其中该医药组成物包括含有至少一个来自HIV-1Nef的分泌修饰区(SMR)胜肽及至少一个凝聚素(Clu)结合蛋白(Clu-BP)的多部分胜肽。
在部分实施方案中,该感染性疾病由细菌引起。在部分实施方案中,该感染性疾病经由真菌引起。在部分实施方案中,该感染性疾病由寄生虫引起。
在部分实施方案中,该感染性疾病由选自以下组成的群组的病毒引起:人类免疫不全病毒1型及2型(HIV-1及HIV-2)、人类T细胞嗜淋巴细胞病毒I型及II型(HTLV-I及HTLV-II)、A型肝炎病毒、B型肝炎病毒(HBV)、C型肝炎病毒(HCV)、D型肝炎病毒(HDV)、E型肝炎病毒(HEV)、G型肝炎病毒(HGV)、细小病毒B19病毒、A型肝炎病毒、G型肝炎病毒、E型肝炎病毒、输血传播病毒(TTV)、爱泼斯坦-巴尔病毒、人类巨细胞病毒1型(HCMV-1)、人类疱疹病毒6型(HHV-6)、人类疱疹病毒7型(HHV-7)、人类疱疹病毒8型(HHV-8)、A型流感病毒(包括亚型H1N1及H5N1)、人类间质肺病毒、严重急性呼吸道综合症(SARS)冠状病毒、汉他病毒及来自沙粒病毒科的RNA病毒(例如拉沙热病毒(LFV))、肺病毒科(例如人类偏肺病毒)、斯状病毒科(例如伊波拉病毒(EBOV)、马尔堡病毒(MBGV)及塞卡病毒);布尼亚病毒科(例如裂谷热病毒(RVFV),克里米亚-刚果出血热病毒(CCHFV)及汉坦病毒);黄病毒科(西尼罗河病毒(WNV)、登革热病毒(DENV)、黄热病病毒(YFV)、GB病毒C(GBV-C;以前称为G型肝炎病毒(HGV)));轮状病毒科(例如轮状病毒),以及前述的组合。在一实施方案中,个体感染HIV-1或HIV-2。
结合疗法
在某些实施方案中,本申请的SMR胜肽与一个或多个其他抗癌剂结合。该抗癌剂可为致死蛋白(Hsp70)抑制剂;烷化剂、蒽环抗生素、抗代谢物、解毒剂、干扰素、多株(polyclonal)或单株抗体、EGFR抑制剂、HER2抑制剂、组蛋白去乙酰酶抑制剂、荷尔蒙或抗荷尔蒙剂、有丝分裂抑制剂、磷脂酰肌醇3-激酶(PI3K)抑制剂、Akt抑制剂、哺乳动物标靶的雷帕霉素(mTOR)抑制剂、蛋白酶体抑制剂、聚(ADP-核糖)聚合酶(PARP)抑制剂、Ras/MAPK路径抑制剂、中心体解簇剂(centrosome declustering agent)、多激酶抑制剂、丝胺酸/苏胺酸激酶抑制剂、酪胺酸激酶抑制剂、VEGF/VEGFR抑制剂、紫杉烷或紫杉烷衍生物、芳香酶抑制剂、蒽环类药物、微管标靶药物、拓朴异构酶毒药、分子标靶或酶(例如激酶或蛋白质甲基转化酶)抑制剂、胞苷类似物及前述的组合。
例示性的致死蛋白(Hsp70)抑制剂包括但不限于,MKT-077(1-乙基-2-[[3-乙基-5-(3-甲基-2(3H)-苯并噻唑亚基(benzothiazolylidene))-4-氧代-2-噻唑烷二基(thiazolidinylidene)]甲基]-氯化吡啶)、奥美拉唑(5-甲氧基-2-[[(4-甲氧基-3,5-二甲基-2-吡啶基)甲基]亚磺酰基]-1H-苯并咪唑)、5-(N,N-二甲基)阿米洛利(DMA)、2-苯基乙炔磺酰胺(PES)、JG-98(Li et al.,ACS Med.Chem.Lett.,(2013)4:1042-1047)。其他致死蛋白抑制剂描述于美国第9,642,843号专利及美国第2012/0252818、2017/0014434、及2018/0002325号专利公开。
例示性烷化剂包括但不限于环磷酰胺(Cytoxan;Neosar);苯丁酸氮芥(Leukeran);美法仑(Alkeran);卡莫斯汀(BiCNU);白消安(Busulfex);洛莫司汀(CeeNU);达卡巴仁(DTIC-Dome);奥沙利铂(Eloxatin);卡莫斯汀(Gliadel);异环磷酰胺(Ifex);甲基二(氯乙基)胺(Mustargen);白消安(Myleran);卡铂(Paraplatin);顺铂(CDDP;铂醇);替莫唑胺(Temodar);噻替哌(Thioplex);苯达莫司汀(特伦达);或链脲佐菌素(Zanosar)。
例示性的蒽环抗生素包括但不限于阿霉素(Adriamycin);阿霉素脂质体(Doxil);双羟蒽醌(Novantrone);博来霉素(Blenoxane);柔红霉素(Cerubidine);柔红霉素脂质体(DaunoXome);放线菌素(Cosmegen);泛艾霉素(Ellence);艾达霉素(Idamycin);普卡霉素(Mithracin);丝裂霉素(Mutamycin);喷司他丁(Nipent);或戊柔比星(Valstar)。
例示性的抗代谢物包括但不限于5-氟尿嘧啶(Adrucil);卡培他滨(Xeloda);羟基脲(Hydrea);硫醇嘌呤(Purinethol);培美曲塞(Alimta);氟达拉滨(Fludara);奈拉滨(Arranon);克拉屈滨(Novaplus);氯法拉滨(Clolar);阿糖胞苷(Cytosar-U);地西他滨(Dacogen);阿糖胞苷脂质体(DepoCyt);羟基脲(Droxia);普拉曲沙(Folotyn);5-氟脱氧尿苷(FUDR);吉西他滨(Gemzar);克拉屈滨(Leustatin);氟达拉滨(Oforta);甲氨蝶呤(MTX;Rheumatrex);甲氨蝶呤(Trexall);硫鸟嘌呤(Tabloid);TS-1或阿糖胞苷(Tarabine PFS)。
例示性的解毒剂包括但不限于阿米福汀(Ethyol)或美司那(Mesnex)。
例示性的干扰素包括但不限于干扰素α-2b(Intron A)干扰素α-2a(Roferon-A)。
例示性的多株或单株抗体包括但不限于曲妥珠单抗(Herceptin);奥法木单抗(Arzerra);贝伐单抗(Avastin);利妥昔单抗(Rituxan);西妥昔单抗(Erbitux);帕尼单抗(Vectibix);托西莫单抗/碘l3l托西莫单抗(Bexxar);阿仑单抗(Campath);替伊莫单抗(Zevalin;In-111;Y-90Zevalin);吉妥珠单抗(Mylotarg);依库丽单抗(Soliris)及Ordenosumab。
例示性EGFR抑制剂包括但不限于吉非替尼(Iressa);拉帕替尼(Tykerb);西妥昔单抗(Erbitux);厄洛替尼(Tarceva);帕尼单抗(Vectibix);PKI-166;坎尼替尼(Cl-1033);马妥珠单抗(Emd7200)或EKB-569。
例示性的HER2抑制剂包括但不限于曲妥珠单抗(赫赛汀);拉帕替尼(Tykerb)或AC-480。
例示性的组蛋白去乙酰酶抑制剂包括但不限于立诺他(Zolinza)、丙戊酸、罗米地辛、恩替司他阿维菌素、吉诺司他及莫西妥他汀。
例示性的荷尔蒙或抗荷尔蒙剂包括但不限于他莫昔芬(Soltamox;Nolvadex);雷洛昔芬(Evista);孕酮(Megace);亮丙瑞林(Lupron;Lupron Depot;Eligard;Viadur);氟维司群(Faslodex);来曲唑(Femara);雷公藤甲素(Trelstar LA;Trelstar Depot);依西美坦(Aromasin);戈舍瑞林(Zoladex);比卡鲁胺(Casodex);阿那曲唑(Arimidex);氟甲睾酮(Androxy;Halotestin);甲羟孕酮(Provera;Depo-Provera);阿比特龙(Zytiga);亮丙瑞林(Lupron);雌莫司汀(Emcyt);氟他胺(Eulexin);托瑞米芬(Fareston);degarelix(Firmagon);尼鲁米特(Nilandron);阿巴瑞克(Plenaxis);或睾丸内酯(Teslac)。
例示性的有丝分裂抑制剂包括紫杉醇(Taxol;Onxol;Abraxane);多西他赛(Taxotere);长春新碱(Oncovin;Vincasar PFS);长春碱(Velban);依托泊苷(Toposar;Etopophos;VePesid);邦莱(Vumon);易莎平(Ixempra);诺考达唑;埃博霉素;长春瑞滨(Navelbine);喜树碱(CPT);伊立替康(Camptosar);拓扑替康(Hycamtin);氨色林或片螺素D(LAM-D)。
例示性的磷脂酰肌醇3-激酶(PI3K)抑制剂包括:渥曼青霉素(一种PI3K不可逆抑制剂)、去甲氧绿胶霉素(一种渥曼青霉素的衍生物)、LY294002,PI3K的可逆抑制剂;BKM120(Buparlisib);艾代拉利司(一种PI3Kδ抑制剂);杜书利西布(IPI-145,PI3Kδ及γ的抑制剂);阿培利西(BYL719),一种α特异性PI3K抑制剂;TGR 1202(以前称为RP5264),一种口服PI3Kδ抑制剂;以及,copanlisib(BAY 80-6946),主要为PI3Kα、δ异构体抑制剂。
例示性的Akt抑制剂包括但不限于米替福新、AZD5363、GDC-0068、MK2206、哌立福新、RX-0201、PBI-05204、GSK2141795及SR13668。
例示性的MTOR抑制剂包括但不限于everolimus(Afmitor)或temsirolimus(Torisel);雷帕霉素、ridaforobmus;deforobmus(AP23573)、AZD8055(阿斯利康)、OSI-027(OSI)、INK-128、BEZ235、PI-103、Torinl、PP242、PP30、Ku-0063794、WAY-600、WYE-687、WYE-354及CC-223。
例示性的蛋白酶体抑制剂包括但不限于硼替佐米(PS-341)、依唑米布(MLN2238)、MLN 9708、地兰佐米(CEP-18770)、卡非佐米(PR-171)、YU101、奥普佐米(ONX-0912)、马里佐米(NPI-0052)及双硫龙。
例示性的PARP抑制剂包括但不限于奥拉帕尼、依尼帕利布(iniparib)、velaparib、BMN-673、BSI-201、AG014699、ABT-888、GPI21016、MK4827、INO-1001、CEP-9722、PJ-34、Tiq-A、Phen、PF-01367338及前述的组合。
例示性的Ras/MAPK抑制剂包括但不限于曲美替尼、selumetinib、cobimetinib、0-1040、PD0325901、AS703026、R04987655、R05068760、AZD6244、GSK1120212、TAK-733、U0126、MEK162及GDC-0973。
例示性的中心体解簇剂抑制剂包括但不限于灰黄霉素;诺司卡宾、诺司卡宾衍生物,例如溴化诺司卡宾(例如9-溴化诺司卡宾)、还原的溴化诺司卡宾(RBN)、N-(3-溴芐基)诺司卡宾、氨基诺司卡宾及其水溶性衍生物;CW069;菲蒽衍生的聚(ADP-核糖)聚合酶抑制剂PJ-34;N2-(3-吡啶基甲基)-5-硝基-2-呋喃酰胺,N2-(2-噻吩基甲基)-5-硝基-2-呋喃酰胺及N2-芐基-5-硝基-2-呋喃酰胺。
例示性的多激酶抑制剂包括但不限于雷戈非尼;索拉非尼(Nexavar);舒尼替尼(Sutent);BIBW 2992;E7080;Zd6474;PKC-412;莫替沙尼或AP24534。
例示性的丝胺酸/苏胺酸激酶抑制剂包括但不限于氟西汀(ruboxistaurin);盐酸艾司地尔;黄酮哌啶醇;seliciclib(CYC202;Roscovitrine);SNS-032(BMS-387032);Pkc4l2;溴他汀;KAI-9803;SF1126;VX-680;Azdl l52;Arry-l42886(AZD-6244);SCIO-469;GW681323;CC-401;CEP-1347或PD 332991。
例示性的酪胺酸激酶抑制剂包括但不限于厄洛替尼(Tarceva);吉非替尼(Iressa);伊马替尼(Gleevec);索拉非尼(Nexavar);舒尼替尼(Sutent);曲妥珠单抗(Herceptin);贝伐单抗(Avastin);利妥昔单抗(Rituxan);拉帕替尼(Tykerb);西妥昔单抗(Erbitux);帕尼单抗(Vectibix);Everolimus(Afmitor);alemtuzumab(Campath);吉妥单抗(Mylotarg);temsirolimus(Torisel);帕唑帕尼(Votrient);达沙替尼(Spry cel);尼洛替尼(Tasigna);瓦他拉尼(Ptk787;ZK222584);CEP-701;SU5614;MLN518;XL999;VX-322;Azd0530;BMS-354825;SKI-606CP-690;AG-490;WHI-P154;WHI-P131;AC-220;或AMG888。
例示性的VEGF/VEGFR抑制剂包括但不限于贝伐单抗(Avastin);索拉非尼(Nexavar);舒尼替尼(Sutent);雷尼单抗;培加帕尼;或凡德他尼。
例示性的微管标靶药物包括但不限于紫杉醇、多西紫杉醇、长春新碱、长春花素、诺考达唑、埃博霉素及那韦尔滨。
例示性的拓朴异构酶毒药包括但不限于替尼泊苷、依托泊苷、阿霉素、喜树碱、柔红霉素、放线菌素、米托蒽醌、氨酚、泛艾霉素及艾达霉素。
例示性的紫杉烷或紫杉烷衍生物包括但不限于紫杉醇及多西紫杉醇。
例示性的一般化疗剂、抗肿瘤剂、抗增殖剂包括但不限于奥曲他敏(Hexalen);异维A酸(Accutane;Amnesteem;Claravis;Sotret);维甲酸(类维生素A);阿扎胞苷(Vidaza);硼替佐米(Velcade);天冬酰胺酶(Elspar);左旋咪唑(Ergamisol);米托坦(Lysodren);丙卡巴嗪(Matulane);培门冬酶(Oncaspar);地尼白介素(Ontak);porfimer(Photofrin);aldesleukin(Proleukin);来那度胺(Revlimid);贝沙罗汀(Targretin);沙利度胺(Thalomid);temsirolimus(Torisel);三氧化二砷(Trisenox);verteporfin(Visudyne);以及,含羞草碱(Leucenol)。
这些其他化疗剂可与本申请的SMR胜肽注入脂质体中、在不同脂质体制剂中与该SMR胜肽共投予、或通过其他方式投予(例如口服投予、静脉注射等)。
在某些特定实施方案中,本申请的SMR胜肽与一个或多个致死蛋白抑制剂结合。
剂量及投予途径
根据疾病标靶的性质,本说明书的多部分胜肽可通过任何途径投予,包括但不限于各种以下途径:肠胃外、胃肠道、吸入及局部(表皮)投予途径。肠胃外投予通常包括注射或输注,且包括例如静脉内、动脉内、瘤内、心内、肌肉内、囊内(例如膀胱)、脑内、脑室内、骨内输注、玻璃体内、关节内、鞘内、硬膜外、皮内、皮下、经皮及腹膜内投予。胃肠道投予包括口服、口腔内、舌下、及直肠投予。投予途径可关于多部分胜肽的局部或全身递送。
作为一般建议,无论是通过一次投予还是多次投予,所投予的多部分胜肽的治疗有效量将处在约1ng/kg体重/天至100mg/kg体重/天的范围内。在一特定实施方案中,投予的多部分胜肽范围为约1ng/kg体重/天至约1μg/kg体重/天、1ng/kg体重/天至约100ng/kg体重/天、1ng/kg体重/天至约10ng/kg体重/天、10ng/kg体重/天至约1μg/kg体重/天、10ng/kg体重/天至约100ng/kg体重/天、100ng/kg体重/天至约1μg/kg体重/天、100ng/kg体重/天至约10μg/kg体重/天、1μg/kg体重/天至约10μg/kg体重/天、1μg/kg体重/天至约100μg/kg体重/天、10μg/kg体重/天至约100μg/kg体重/天、10μg/kg体重/天至约1mg/kg body体重/天、100μg/kg体重/天至约10mg/kg体重/天、1mg/kg体重/天至约100mg/kg体重/天及10mg/kg体重/天至约100mg/kg体重/天。
在其他实施方案中,多部分胜肽以如下剂量范围投予:每次注射1ng-10ng、每次注射10ng-100ng、每次注射100ng-lμg、每次注射1μg-10μg、每次注射10μg-100μg、每次注射100μg-l mg、每次注射1mg-10mg、每次注射10mg-100mg、及每次注射100mg-1000mg。可每天注射多部分胜肽、或者每2、3、4、5、6及7天注射多部分胜肽。
在其他实施方案中,所投予的多部分胜肽的剂量范围为约1ng/kg至约100mg/kg。在还一特定实施方案中,所投予的抗体的范围为约1ng/kg至约10ng/kg、约10ng/kg至约100ng/kg、约100ng/kg至约1μg/kg、约1μg/kg至约10μg/kg、约l0μg/kg至约100μg/kg、约100μg/kg至约1mg/kg、约1mg/kg至约10mg/kg、约10mg/kg至约100mg/kg、约0.5mg/kg至约30mg/kg、及约1mg/kg至约15mg/kg。
在其他特定实施方案中,所投予的多部分胜肽的量为以下或约为以下:0.0006、0.001、0.003、0.006、0.01、0.03、0.06、0.1、0.3、0.6、1、3、6、10、30、60、100、300、600及1000mg/天。
多部分胜肽的具体剂量通过个体病患的特定情况决定,包括病患的大小、体重、年龄及性别、疾病的性质及阶段、疾病的侵袭性、以及投予医药组成物的途径。
在某些实施方案中,多部分胜肽可每天投予至少一次,通常每天投予一次、二次、三次或四次,且在整个白天及晚上以相等的间隔给予剂量,以维持药物的恒定存在,进而提供足够的疗效。然而,技术人员应当理解,可针对任何病患优化治疗方案,且化合物的投予可低于每天一次。
如本文使用的剂量单位形式包括适合作为待治疗受试者的单位剂量的物理上离散的单元;每个单元含有预定量的多部分胜肽,该预定量经计算可与所欲药物载剂一起产生所欲治疗效果。本发明的剂量单位形式的说明书直接取决于多部分胜肽的独特特征及欲实现的特定治疗效果。
本说明书的多部分胜肽的毒性及治疗功效可通过细胞培养物或实验动物中的标准药学程序来确定,例如:用于确定LD50(对50%群体致死的剂量)及ED50(对50%的群体有治疗效果的剂量)。毒性及治疗效果之间的剂量比为治疗指数,且可表示为LD50/ED50比。较佳为表现出大治疗指数的胜肽。虽然可以使用表现出有毒副作用的胜肽,但应该注意设计出将这些胜肽标靶至受影响组织部位的递送系统,以使对非病变细胞的潜在损害最小化,从而减少副作用。
从细胞培养测定及动物研究获得的数据可用于配制用于人类的剂量范围。这些胜肽的剂量较佳在包括ED50且几乎没有毒性或没有毒性的循环浓度范围内。剂量可在该范围内变化,此取决于所用的剂型及所用的投予途径。对于本说明书的方法中所使用的任何胜肽,最初可根据细胞培养测定估计治疗有效剂量。可在动物模型中配制剂量以达到循环血浆浓度范围,该范围包括在细胞培养中测定的IC50(即,达到症状的半数最大抑制的测试化合物浓度)。这些信息可用于更准确地确定人体中的有用剂量。医药组成物可与投予说明书一起包括在容器、包装或分配器中。
当治疗癌症时,可开处方将本说明书的任何多部分胜肽与一种或多种其他抗癌剂合并使用。当在此种结合疗法中使用时,本说明书的多部分胜肽及其他试剂可在治疗期间通过相同或不同途径同时投予或在不同时间投予。特别地,多部分胜肽可与如下物质结合投予:致死蛋白siRNA、抗癌剂例如烷化剂、蒽环抗生素、抗代谢物、解毒剂、干扰素、多株(polyclonal)或单株抗体、EGFR抑制剂、HER2抑制剂、组蛋白去乙酰酶抑制剂、荷尔蒙或抗荷尔蒙剂、有丝分裂抑制剂、磷脂酰肌醇3-激酶(PI3K)抑制剂、Akt抑制剂、哺乳动物标靶的雷帕霉素(mTOR)抑制剂、蛋白酶体抑制剂、聚(ADP-核糖)聚合酶(PARP)抑制剂、Ras/MAPK路径抑制剂、中心体解簇剂(centrosome declustering agent)、多激酶抑制剂、丝胺酸/苏胺酸激酶抑制剂、酪胺酸激酶抑制剂、VEGF/VEGFR抑制剂、紫杉烷或紫杉烷衍生物、芳香酶抑制剂、蒽环类药物、微管标靶药物、拓朴异构酶毒药、分子标靶或酶(例如激酶或蛋白质甲基转化酶)抑制剂、及前述的组合。
在部分实施方案中,本说明书的多部分胜肽与化疗剂(例如紫杉醇或顺铂)结合投予或同时投予。
同样地,当治疗感染性疾病时,可开处方将本说明书的多部分胜肽与一种或多种抗病毒药物结合使用。在某些实施方案中,抗病毒药物选自以下组成的群组的抗逆转录病毒药物:蛋白酶抑制剂、核苷逆转录酶抑制剂、核苷酸逆转录酶抑制剂、非核苷酸逆转录酶抑制剂、整合酶抑制剂、进入抑制剂、及成熟抑制剂。例示性的抗病毒药物包括但不限于,阿巴卡韦、阿昔洛韦、阿德福韦、金刚烷胺、阿莫考韦、安普那韦、抗蛋白酶、阿立他滨、阿比多尔、青蒿素、阿扎那非、亚翠佩、叠氮胸苷(AZT)、贝韦立马、波普瑞韦、丁基化羟基甲苯(BHT)、西多福韦、卡贝兹、地瑞纳韦、地拉韦定、地达诺新、阿德福韦酯、二十二烷醇、依多西定、依法韦仑、埃替拉韦、艾夫他滨、恩曲他滨、恩福韦里肽、恩替卡韦、依曲韦林、泛昔洛韦、邻甲酸钠、福沙那韦、丙氧鸟苷、格娄博丹A、GSK-572、艾维西林、HIV融合抑制剂、金丝桃素、伊巴里佐昔、脱氧碘尿核苷、衣努诺韦、英地那韦、干扰素(I型,II型和III型)、拉米夫定、勒西韦林、伊普列韦、洛韦利、马拉维罗克、马里巴韦、MK-2048、莫利克森索(NOV-205)、莫罗韦、奈尔芬纳韦、奈韦拉平、奈克斯韦、非核苷酸HIV RT抑制剂、奥司他韦、聚乙二醇化干扰素(例如,聚乙二醇化干扰素α-2a)、彭西洛韦、潘昔洛韦、帕拉米韦、不列康纳利、鬼臼毒素、雷西韦、雷特格拉韦、雷基莫德、利巴韦林、利福平、利比韦林、利曼替丁、利托那韦、沙奎尼韦、雌吡啶、斯塔夫定、塔里巴韦林、替诺福韦、替普兰纳韦、三氟脲苷、三噻韦;洛曼替丁、特卢韦达、瓦拉西洛韦(Valtrex)、瓦兰西洛韦、维克里韦罗韦、韦达拉宾、维韦康、扎尔西塔滨、扎纳米韦(Relenza)、齐多夫定、以及前述的组合。
治疗可进行足以达到治疗效果的时间。一般而言,预期治疗将在疾病状态持续时无限期地继续,但如果医药组成物不再产生有益效果,则可指示停止。主治医生将根据病患的反应知道如何增加、减少或中断治疗。
多部分胜肽的制备
本说明书的多部分胜肽可化学合成或由用编码多部分胜肽的多核苷酸表达载体转染的细胞产生。可使用传统的液相或固相合成来合成本说明书的多部分胜肽。Fmoc及t-Boc固相胜肽合成(SPPS)可用于自羧基到胺基终端使胜肽生长。
在其他实施方案中,使用本领域技术人员周知的重组DNA技术合成多部分胜肽。可设计多核苷酸表达载体以促进许多不同细胞宿主中的制备表达水平,该宿主包括细菌、酵母菌、昆虫细胞、及哺乳动物细胞。
在一方面,本说明书提供了用编码多部分胜肽的多核苷酸或表达载体转染的宿主细胞。宿主细胞可为能够表达本文所述的多部分胜肽编码核酸或表达载体的任何细菌或真核细胞。
在另一方面,根据本发明的制备多部分胜肽的方法包括在允许产生多部分胜肽的条件下培养用编码多部分胜肽的多核苷酸或表达载体转染的宿主细胞,并从培养的细胞中纯化胜肽。该胜肽可以通过瞬时或稳定表达多部分胜肽的细胞来产生,并从培养的细胞中纯化胜肽。可使用任何能产生功能胜肽的细胞。表达胜肽的细胞可为原核或细菌来源的(例如大肠杆菌),或者其可为真核或哺乳动物来源的(例如人类细胞)。在其他实施方案中,细胞为酵母菌细胞或昆虫细胞。当细胞为真核来源时,产生胜肽的细胞较佳用多核苷酸稳定转染以表达胜肽。
通过以下实施例进一步说明本说明书内容,这些实施例不应解释为限制性的。本申请全文引用的所有参考文献、专利、及公开的专利申请内容及附图与表格在此引入作为参考。
实施例1:实施例2-8的材料与方法
1-1.细胞株、试剂及抗体MCF-7细胞株,非侵入性雌激素受体阳性(ER+)及MDA-MB-231细胞株(ER阴性)购自美国典型培养物保藏中心(ATCC,Manassas,VA)。MCF-10A细胞株,非致瘤性上皮细胞株也购自ATCC。3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四唑(MTT)。具有高葡萄糖的Dulbecco's改良伊格培养基(DMEM)及FLUOROBRITETM无酚红DMEM(MCF-7)购自Thermo Fisher Scientific(Rockford,IL)。RPMI 1640培养基(MDA-MB-231细胞)获自LifeTechnologies Company(Carlsbad,CA)。基础培养基MEBM及添加剂MEGM(MCF-10A细胞)获自Lonzal/Clonetics Corporation(Lonza,Walkersville,MD)。紫杉醇购自Sellck-Chemon,(Houston,TX)。顺铂购自EMD/Millipore(Billerica,MA)。膜联蛋白V-FITC/PI Apopto及PI细胞周期试剂盒购自Nexcelom Bioscience(Lawrence,MA)。CD63兔多株抗体及Alix山羊多株抗体购自Santa Cruz Biotechnology Inc.(Santa Cruz,CA)。PEG-SMRwt-Clu PEG-SMRwt及PEG-SMRmut HIV-l Nef胜肽购自InnoPep Company(San Diego,CA)。
1-2.细胞培养将细胞在上述培养基中培养,加入无胞外体的胎牛血清(SystemBiosciences Inc.,Mountain View,CA)、100单位/mL青霉素及100mg/mL链霉素,并保持在37℃及5%CO2的湿润气氛中。
1-3.存活率及增殖将人类乳癌细胞株接种至96孔盘(5000个细胞/孔)中,并用各种浓度的SMR胜肽(包括PEG-SMRwt-Clu、PEG-SMRwt及PEG-SMRmut)处理24小时,以测定IC50(抑制浓度)。使用MTT试验(Molecular Devices,Sunnyvale,CA)测定细胞增殖。用MTT单独处理的细胞及未处理的细胞进行对照实验,并在此基础上,使用24小时及48小时的培养时间于胜肽处理细胞的MTT试验(Stockerta JC.et al,2012and Riss TL.et al,2015)。
1-4.细胞周期分析将MCF-7及MDA-MB-231乳癌细胞以每孔4x105个细胞培养到6孔盘中,并用紫杉醇及顺铂各自处理或与PEG-SMRwt-CLU胜肽结合处理24及48小时。使用碘化丙啶细胞周期试验进行细胞周期分析,并使用Cellometer(Nexcelom,MA)测量。用IC50浓度的SMR进行进一步的实验:结果显示在MCF-7细胞上有1.12μM的PEG-SMRwt-Clu、0.28μM的PEG-SMRwt,持续24小时,并在MDA-MB-231细胞上有0.28μM的PEG-SMRwt-Clu、0.42μM的PEG-SMRwt,持续24小时,每个细胞时间两个阶段。将乳癌细胞以5x103个细胞/ml接种至96孔盘中,并用1.6μM/ml紫杉醇或3mg/ml顺铂处理、或者以1.12μM/ml的PEG-SMR-CLU胜肽、SMR胜肽与紫杉醇或顺铂(MCF-7细胞)进行处理。或者,对于MDA-MB-231细胞,使用1.6μM/ml紫杉醇或2mg/ml顺铂、或0.28μM/ml的PEG-SMR-CLU胜肽、或与这些药物中的每一种组合的胜肽。对于不同细胞类型,顺铂及紫杉醇的浓度通过实验确定IC50剂量(数据未显示)。在24小时或48小时培养结束时,通过Cellometer成像细胞仪试验评估细胞。
全部上述步骤独立地在MCF-7及MDA-MB-231细胞上进行。为了进一步了解这些胜肽是否与化疗药物有协同作用,6组癌细胞处理如下:1)未处理,2)PEG-SMRwt-CLU,3)紫杉醇,4)紫杉醇与PEG-SMRwt-CLU的组合,5)顺铂,6)顺铂与PEG-SMRwt-CLU的组合。
1-5.评估细胞凋亡将乳癌细胞以每孔4x105个细胞接种到6孔盘中,并用紫杉醇或顺铂或各种浓度的SMR胜肽处理24小时或不同的时间点。SMR如上所述。使用AnnexinV-FITC检测试剂盒(Nexcelom,MA)测定细胞凋亡,并通过Cellometer成像细胞仪试验可视化。
1-6.胞外体分离及纯化如先前描述(Ali SA.et al,2010)通过差速离心自乳癌细胞中分离胞外体。未处理的肿瘤细胞用作对照。简言之,将上述处理及未处理的细胞上清液以400x g离心10分钟。将上清液转移到透明管中并以10,000x g离心30分钟。将来自第二次旋转的上清液以200,000x g超速离心2小时,以沉淀胞外体。最后,使用PBS重新悬浮胞外体沉淀,并在4℃下储存至用于分析。
1-7.通过乙酰胆碱酯酶(AchE)测定的胞外体表征如所述般地(Ellman et al,1961)通过测量AchE来定量纯化的胞外体。简言之,制备100mM二硫代硝基苯甲酸(DTNB)溶液用作颜色指示剂母液,并制备在PBS溶液中的28.9mg/mL乙酰硫代胆碱碘化物作为基质母液。基质母液可在-20℃下储存最长达一个月,而颜色指示剂可以在4℃下储存两周。通过将10mL的PBS与200μL底物及500μL的DTNB混合制备工作溶液。将50μL的各种胞外体样品转移到96孔微量滴定板中,并使用AchE自0.98mU/mL至2000mU/mL制备标准曲线。将50μL的标准品加入分开的孔中,向所有孔中加入200μL的工作溶液。培养20分钟后,使用SpectroMax M5荧光仪在450nm下测量AchE活性。
1-8.胞外体奈米颗粒追踪分析(NTA)使用具有NTA23的NanoSight LM10(NanoSight Ltd.,Minton Park,UK)进行胞外体的绝对尺寸分布分析。基于布朗运动及扩散系数自动追踪及确定粒子尺寸。分离后,将未处理及处理的乳癌胞外体重新悬浮于0.5mL的PBS中。对照培养基及过滤的PBS用作该技术中的对照。NTA测量条件为:温度=21.0+/-0.5℃;黏度=0.99+/-0.01cP,每秒帧数=25,测量时间=30s。全部的样品检测阈值相似。每个样品纪录两次。
1-9.西方墨点法分析如上述,自培养上清液中分离胞外体,通过测量280nm处的吸光度来确定蛋白质浓度(Nanodrop 2000)。通过在95°C加热15分钟,在SDS-PAGE样品缓冲液中使蛋白质样品变性。使用标准TGX预制凝胶(4-20%Bio-Rad,Richmond,CA)分离蛋白质并如先前描述进行墨点法(Huang MB.et al 2004)。将墨点与一抗、抗CD63及抗Alix一起培养,然后与山羊或兔抗Ig二抗一起培养。使用ECL化学发光底物(Santa CruzBiotechnology,Santa Cruz,CA)检测特异性条带,并在ImageQuant LAS 4000成像系统(GEHealthcare,Piscataway,NJ 08854)上可视化。
1-10.荧光N-Rh-PE测量荧光磷脂类似物N-Rh-PE[N-(丽丝胺罗丹明B磺酰基)磷脂酰乙醇胺]为如先前描述的胞外体及多囊泡体的腔内囊泡脂质标记物(Willem J et al,1990)。简言之,将10mM的N-Rh-PE储存在氯仿/甲醇(2:1)中。然后,将在预冷却的反应介质中的5μM的N-Rh-PE溶液加入用siRNA-Negative或siRNA-HSPA9转染处理过的MCF-7乳癌细胞,然后在4℃培养1小时。在该培养后,除去培养基并用冷培养基充分洗涤细胞以除去过量的未结合脂质。将标记的细胞在含有10%的胞外体去除的FBS培养基(经热失活)的完全RPMI1640中于37℃下培养过夜。使用光谱仪分别在550nm及590nm激发及发射波长对所收集的上清液/胞外体中的N-Rh-PE进行测量。
1-11.致死蛋白抗体转染使用Chariot试剂盒(Active Motif,Carlsbad,CA)根据制造商的程序以致死蛋白抗体转染MCF-7乳癌细胞。培养这些细胞48小时之后,分离胞外体并通过AchE测定及NanoSight分析进行测量。
1-12.小干扰RNA(siRNA)瞬时转染使用Amaxa的Nucleofector试剂盒(LonzaWalkersville Inc.,Walkersville,MD)根据制造商的程序以双链siRNA转染MCF-7乳癌细胞。如供应商所推荐般地,使用Amaxa Biosystems Nucleofector II进行质体转染。如前所述制备致死蛋白siRNA(Shelton et al,J Virol(2012)86(1):p.406-19)。转染后,将细胞在37℃下培养24、48、72及96小时,分离胞外体并通过AchE测定及西方墨点法测量。
1-13.统计分析数据表示为平均值±标准偏差(S.D.)。假设方差相等的双样本t-检验用于比较每组中对照及处理样品之间的差异。p≤0.05的值被认为具有统计学上的显著性。
实施例2:SMR胜肽抑制乳癌细胞的细胞生长
作为对照,将乳癌细胞以提升浓度(35nM/mL、70nM/mL、140nM/mL、280nM/mL、560nM/mL及1120nM/mL)的PEG-SMRwt-Clu胜肽结合PEG-SMRwt或PEG-SMRmut进行处理24小时。含有SMRwt序列的二胜肽在剂量依赖的方式中抑制了乳癌细胞生长(图1)。对于MCF-7细胞而言,在1.12μM/mL的PEG-SMRwt-Clu、及0.28μM/mL的PEG-SMRwt的情况下观察到50%的抑制作用。对于MDA-MB-231细胞而言,在0.28μM/mL的PEG-SMRwt-Clu、及0.42μM/mL的PEG-SMRwt的情况下观察到50%的抑制作用。该PEG-SMRmut胜肽无抑制增殖作用。
实施例3:SMRwt胜肽在乳癌细胞中诱导细胞周期停滞
数据表示PEG-SMRwt-Clu胜肽在MCF-7细胞及MDA-MB-231细胞中诱导细胞周期停滞,其于48小时进行测定(图2)。当细胞经PEG-SMRwt-Clu胜肽、或该胜肽结合紫杉醇或顺铂进行处理时,其阻挡于G2/M期,表示PEG-SMRwt-Clu胜肽会诱导乳癌细胞的G2/M停滞。
实施例4:SMRwt胜肽在MCF-7乳癌细胞中提升乳癌细胞对于顺铂及紫杉醇的敏感性
在不同的实验中,将MCF-7及MDA-MB-231细胞单独以PEG-SMRwt-CLU或PEG-SMRmut-CLU进行处理、或者进一步结合紫杉醇或顺铂进行处理,而后通过Annexin V-FITC/PI试验对细胞凋亡进行测定。相对于未经修饰的对照胜肽,在使用紫杉醇及顺铂培养48小时之后,此二细胞株均显示出提升的细胞凋亡(图3)。有趣地,PEG-SMRwt-Clu胜肽在MCF-7细胞中提升了药物诱导细胞凋亡的水平,但在MDA-MB-231细胞则否。
实施例5:SMRwt胜肽在乳癌细胞中阻挡胞外体释放
进行乙酰胆碱酯酶(AchE)试验、NanoSight分析及西方墨点法分析,以确定使用各种胜肽处理48小时的MCF-7及MDA-MB-231乳癌细胞所释放的胞外体的特征。该结果表示胞外体释放受到SMRwt胜肽抑制。
对在胞外体中的AchE活性进行测定,且此分析结果显示于图4A及4B。在MCF-7细胞中,发现对照胞外体含有113.49mU/mL的AchE活性。反之,发现以PEG-SMRwt-CLU胜肽处理的细胞有41.95mU/mL的活性;以PEG-SMRwt-CLU结合紫杉醇处理的细胞有51.87mU/mL的活性;以及,以PEG-SMRwt-CLU结合处理的细胞有16.95mU/mL的活性(图4A)。在MDA-MB-231细胞中,对照胞外体含有118.48mU/mL的AchE活性,然而,发现以PEG-SMRwt-CLU胜肽处理的细胞有66.77mU/mL的活性;以PEG-SMRwt-CLU胜肽结合紫杉醇处理的细胞有64.15mU/mL的活性;以及,以PEG-SMRwt-CLU结合顺铂处理的细胞有27mU/mL的活性(图4B)。
胞外体浓度及尺寸分布的分析通过NanoSight LM10奈米颗粒追踪分析(NTA)进行测定。使用NTA,可根据布朗运动及相关的扩散系数自动追踪及确定粒子尺寸。在通过NTA分析样品之前,确定来自PBS的盐聚集体对背景值没有影响,且设备没有污染物颗粒。未处理的MCF-7细胞对照培养基显示相当数量的颗粒(5.16x109个颗粒/ml)(图4的图表C)。然而,在用PEG-SMRwt-CLU处理(3.28x108个颗粒/ml,p<2.40E-06)、在用PEG-SMRwt-CLU结合紫杉醇处理(5.7x108个颗粒/ml,p<0.0008)、及在用PEG-SMRwt-CLU结合顺铂处理(3.77x108个颗粒/ml,p<0.0001)的MCF-7细胞中发现数量减少的颗粒(图4C)。
类似地,即便来自MDA-MB-231培养物的对照培养基也显示出相当数量的颗粒(4.7x109个颗粒/ml),但在用PEG-SMRwt-CLU胜肽处理(6.8x108个颗粒/ml,p<3.96E-05)、用PEG-SMRwt-CLU胜肽与紫杉醇处理(7.5x108个颗粒/ml,p<0.001)、及用PEG-SMRwt-CLU胜肽与顺铂结合处理(3.06x108个颗粒/ml,p<5.37E-05)(图4的图表D)的MDA-MB-231细胞中发现了减少数量的颗粒。通过NTA分析,在两种乳癌细胞株中,胞外体的尺寸估计在30至47nm的范围。
最后,使用西方墨点法分析检测对照培养物及胜肽处理培养物中的胞外体蛋白。该分析的结果表示,在自MCF-7细胞(图5)及MDA-MB-231细胞(图6)分离的全部胞外体中存在人类CD63及Alix标记物。对照胞外体显示了来自MCF-7细胞的人类CD63的更高表达,及来自MDA-MB-231细胞的Alix的更高表达。
实施例6:阻挡SMR-致死蛋白相互作用阻挡了乳癌细胞中的胞外体释放
先前的研究鉴定了HSP70家族蛋白,致死蛋白(由HSP9编码)作为HIV-1Nef SMR的结合配偶体,并显示了HIV-1Nef SMR-致死蛋白结合的破坏干扰了胞外体释放(Shelton etal,J Virol(2012)86(1):p.406-19)。为了测试类似的相互作用是否负责所观察到的PEG-SMRwt-CLU对来自乳癌细胞的胞外体释放的影响,使用抗致死蛋白的抗体或抗α-微管蛋白的抗体(作为对照)转染MCF-7细胞。通过AchE试验测量,发现抗致死蛋白处理细胞在胞外体释放中显著受损(图7的图表A),并且当通过NTA试验测量时略低(图7的图表B)。抗致死蛋白处理的效果类似于用PEG-SMRwt-CLU胜肽处理MCF-7细胞的效果。
为了进一步验证此致死蛋白介导的过程在癌细胞中的重要性,通过使用表达致死蛋白siRNA的质体构建转染MCF-7细胞来剔除致死蛋白的表达。发现致死蛋白siRNA阻挡了胞外体分泌,如通过AchE试验及膜荧光(N-Rh-PE)试验在所测试的全部时间点(图8的图表A及图8的图表B)且没有任何细胞毒性(图8的图表C)所证实。通过西方墨点法分析,进一步测定来自siRNA转染细胞胞外体的致死蛋白及胞外体标记物CD63(四跨膜蛋白)的表达。该分析的结果显示,自第48小时一直到96小时,致死蛋白及CD63的表达均显著降低(图8的图表D及图8的图表E)。
实施例7:实施例8-14的材料及方法
7-1.细胞株、血清、化学物质及抗体MDA-MB-231、MCF-7、MCF-10A及K562细胞购自美国典型培养物保藏中心(ATCC,Manassas,VA)。将细胞在37℃及5%CO2下培养于RPMI1640(Thermo Fisher Scientific,Rockford,IL),并补充10%热失活的FBS(MedSupplyPartners(Atlanta,GA))、1%麸酰胺酸、100mg/ml青霉素、及100mg/ml链霉素(LifeTechnologies Company,Carlsbad,CA)。使用正常人类血清(NHS)(MedSupply Partners(Atlanta,GA))作为补体蛋白的来源。热失活的正常人类血清(NIS)通过在56℃下加热血清45分钟来制备。兔多株抗致死蛋白抗体(anti-Grp75)购自Abeam,Inc.,(Cambridge,MA);山羊多株抗alix抗体及小鼠单株抗α-微管蛋白抗体购自Sigma-Aldrich,Inc.,(Louis,MO)。过氧化酶共轭山羊抗小鼠IgG、过氧化酶共轭兔抗山羊IgG、及FITC-共轭山羊抗小鼠IgG购自Thermo Fisher Scientific,Inc.,(Rockford,IL)。
7.2.胜肽PEG-SMRwt-Clu、PEG-SMRmut-Clu、SMRwt-CPP、及SMRmut-CPP胜肽通过InnoPep Inc.(San Diego,CA)客制(图9)。
7.3.致死蛋白(HSPA9)DNA构建体使用来自Life Technologies Corporation(Carlsbad,CA)的BLOCK-iT Pol II miR RNAi表现载体套组以及致死蛋白(HSPA9)引子Hmi408224至Hmi 408227以产生具有观酶素(spectinomycin)抗性的表现载体(miR-mortalin),其是表现致死蛋白的microRNA(miRNA;miR)。该套组也含有对应于pcDNA6.2-GW/miR-阴性对照质体(miR-neg),其经预测不会标靶至任何已知脊髓动物基因。
7-4.细胞增殖及细胞毒性试验将人类乳癌细胞株MCF-7、MDA-MB-231、及白血病K562细胞,以及非致瘤MCF-10A细胞接种至96孔盘(5000个细胞/孔),并使用0-1120nM的SMRwt-CPP或SMRmut-CPP进行处理24小时(图10)。使用MTT[3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四唑溴化物]染剂试验通过SpectraMax M5荧光读盘仪(MolecularDevices.Sunnyvale,CA)确定细胞增殖。细胞存活率通过活细胞的粒线体脱氢酶将黄色的MTT转化为紫色的甲(MTT试验)来评估。使用经处理或未经处理的细胞以MTT来进行对照实验,且在此基础上,使用24小时的培养时间于胜肽处理细胞的MTT试验(Huang,M.B.,etal,Oncotarget,2017.8(7):pp.11302-11315.)。自三次独立实验确定结果的统计显著性,其中在各个实验包括三个一组或四个一组。
7.5.胞外体分离及纯化胞外体使用ExoQuick-TC胞外体纯化套组(SystemBiosciencences[SBI],Mountain View CA)或miRCURY胞外体分离套组(EXIQON,Woburn,MA)根据制造商的程序自乳癌细胞及白血病细胞中分离。将未经处理的肿瘤细胞用作对照。简言之,经处理及未经处理的细胞培养上清液(10mL)以3000x g离心15分钟。将所获的上清液转移至干净的管中,添加2mL的ExoQuick-TC缓冲液,混合并于4℃下培养过夜。培养后,将样品内容物以1500x g离心30分钟,取出上清液,将沉淀以1500xg离心5分钟,而后移除上清液的任何痕迹(SBI)。替代地,经处理及未经处理的细胞培养上清液以10,000x g离心5分钟以移除细胞碎片,将上清液(10mL)转移至新的管中,并添加4mL的沉淀缓冲液(EXIQON),且混合内容物及在4℃下培养过夜。培养后,将样品内容物以10,000x g离心30分钟(EXIQON)。将含有胞外体的沉淀重新悬浮至PBS中并储存于4°C或-80℃。
7-6.通过乙酰胆碱酯酶(AchE)测定的胞外体表征如先前描述(Huang et al,Oncotarget,2017.8(7):pp.11302-11315),将经纯化的胞外体通过AchE测量来量化。简言之,制备100mM二硫代硝基苯甲酸(DTNB)溶液用作颜色指示剂母液,并制备在PBS溶液中含有28.9mg/mL乙酰硫代胆碱碘化物作为基质母液。基质母液可在-20℃下储存最长达一个月,而颜色指示剂可以在4℃下储存两周。通过将10mL的PBS与200μL底物及500μL的DTNB混合制备工作溶液。将50μL的各种胞外体样品转移到96孔微量滴定板中,并使用AchE自0.98mU/mL至2000mU/mL制备标准曲线。将50μL的标准品加入分开的孔中,向所有孔中加入200μL的工作溶液。培养20分钟后,使用SpectroMax M5荧光仪在450nm下测量AchE活性(图11)。
7.7通过西方墨点法的蛋白质分析如上述,自培养上清液中分离胞外体,通过测量280nm处的吸光度来确定蛋白质浓度(Nanodrop 2000)。将经培养的细胞使用PEG-SMR-Clu、SMR-CPP胜肽、MKT-077、奥美拉唑或DMA在37℃下处理48小时。为了评估致死蛋白、波形蛋白、及胞外体表现,分别使用抗致死蛋白(Grp-75)、抗波形蛋白及抗Alix抗体进行西方墨点法分析(图12)。
为了收集经历补体攻击的自细胞分泌的蛋白质,细胞在37℃用抗CXCR4抗体及正常人类血清或热失活的人类血清处理10分钟。然后使用PBS洗涤细胞及悬浮于培养基中并在37℃下培养。20分钟后,通过350x g的离心5分钟移除细胞(图15)。
通过在样品缓冲液中于95℃下培养5-10分钟来制备胞外体及细胞裂解物。将该裂解物在还原条件下(150mM DTT)在4-20%CriterionTMTGXTM预制凝胶(BioRad,Hercules,CA)中进行SDS-PAGE,然后转移到硝酸纤维素膜(Bio-Rad,Hercules,CA)上。在含有0.05%Tween 20(TBST)的TBS中,以5%脱脂牛奶(MedSupply,Atlanta,GA)于室温下对硝酸纤维素膜进行阻断1小时。对于细胞裂解物,用抗致死蛋白(Grp-75)单株抗体或抗α-微管蛋白抗体处理膜(图15,图表A及B),或者,对于胞外体,用抗Alix及抗波形蛋白或抗致死蛋白处理膜(图12),而后使用过氧化酶共轭的山羊抗小鼠IgG进行处理。使用ECL化学发光底物(SantaCruz Biotechnology,Santa Cruz,CA)显影条带,并将其暴露于ImageQuant LAS4000成像系统(GE Healthcare,Piscataway,NJ 08854)。
7-8.通过流式细胞仪的细胞凋亡试验为了评估细胞凋亡,将MCF-7及MDA-MB-231乳癌细胞接种至6孔盘(每孔4x105个细胞),并使用以下处理细胞48小时:925nM/mL的MKT-077(于MDA-MB-231细胞)、500nM/mL的MKT-077(于MCF-7细胞)、337.5nM/mL的MKT-077(于K562细胞)、300μM/mL的DMA、200μM/mL的奥美拉唑、1.6μM/mL的紫杉醇、2mg/mL的顺铂、或各自使用三种致死蛋白抑制剂与紫杉醇或顺铂结合处理。细胞凋亡使用TUNEL检测套组(Nexcelom,MA)及GUAVA easyCyte HT(EMD Millipore Corporation,Temecula,CA)系统进行荧光检测来确定(图13)。
7-9.补体介导的细胞毒性试验如先前所述(Reiter et al,Mol Immunol.(1992)29(6):p.771-81)进行补体介导的细胞毒性试验。简言之,将MCF-7、MDA-MB-231及K562细胞进行空载体转染(mock-transfected)或使用致死蛋白siRNA进行转染。将细胞与1μg/ml的抗CXCR4抗体在4℃下进行培养30分钟,而后单独使用PEG-SMRwt-Clu胜肽或PEG-SMRmut-Clu胜肽或SMRwt-CPP或SMRmut-CPP、或者将SMR胜肽与来自正常人类血清(NHS)或热失活正常人类血清(NIS)的补体在37℃下处理60分钟。细胞裂解的百分比使用TC10TM自动细胞技术器(Bio-Rad,Richmond CA)通过台酚蓝排除法来确定(图14、图15的图表D)。
7-10.使用致死蛋白的小干扰RNA(siRNA)的瞬时转染将MDA-MB-231、MCF-7乳癌细胞及K562细胞与无胞外体的培养基置入T-75培养瓶中。在37℃的培养器中24小时之后,使用Amaxa的Nucleofector试剂盒(Lonza Walkersville Inc.,Walkersville,MD)以表现双股致死蛋白siRNA(参见章节7-3)根据制造商的程序对细胞进行转染。空载体转染细胞(“空载体”)或以非致死蛋白siRNA表现载体处理的细胞用作阴性对照。转染后,在通过西方墨点法分析(图15,图表A)及AchE试验(图15,图表C)进行评估之前,将细胞于37℃下在培养基中培养72小时。
7-11.胞外体奈米颗粒追踪分析(NTA)胞外体(300μL)的绝对尺寸分布的分析使用具有NTA2.3的NanoSight LM10(NanoSight Ltd.,Minton Park,UK)进行。基于布朗运动及扩散系数自动追踪及确定粒子尺寸。分离后,将未处理及处理的乳癌细胞或白血病细胞胞外体重新悬浮于0.5mL的PBS中。对照培养基及过滤的PBS用作该技术中的对照。NTA测量条件为:温度=21.0+/-0.5℃;黏度=0.99+/-0.01cP,每秒帧数=25,测量时间=30s。全部的样品检测阈值相似。每个样品纪录两次(图15,图表C)。
7-12.细胞迁徙试验使用InnoCyte细胞迁徙试验(EMD Millipore Corporation,Temecula,CA)根据制造商的程序进行细胞迁徙试验。简言之,细胞迁徙是于SMRwt胜肽或红海海绵蛋白A(正对照抑制剂)存在及不存在的情形下进行监测,其中SMRwt胜肽或红海海绵蛋白A添加至96孔盘的下层腔室。MCF-7及MDA-MB-231乳癌细胞与非致瘤MCF-10A乳细胞通过0.25%的Trypsin-EDTA(Life Technologies)释放来收集,并重新悬浮至无血清的RPMI1640培养基中(250,000-500,000个细胞/ml)。一共250,000-500,000个细胞添加至上层腔室中,且使其在37℃及5%CO2的气氛下通过8μm的孔径膜进行迁徙24小时。分离通过膜迁移的细胞,并用Calcein-AM荧光染剂标记。使用荧光读盘仪(Molecular Devices,Sunnyvale,CA)在激发波长为485nm及发射波长为515nm的条件下测量荧光。实验重复进行三次,且每个条件实验为一式四份进行。
13.统计分析数据表示为平均值±标准偏差(S.D.)。假设方差相等的双样本t-检验用于比较每组中对照及处理样品之间的差异。p≤0.05的值被认为具有统计学上的显著性。
实施例8:SMRwt-CPP胜肽在乳癌及白血病细胞株中抑制细胞增殖及生长
将MCF-7及MDA-MB-231乳癌细胞与K562白血病细胞培养物以提升浓度(35nM/mL、70nM/mL、140nM/mL、280nM/mL、560nM/mL及1120nM/mL)的SMRwt-CPP胜肽或阴性对照胜肽SMRmut-CPP处理24小时。如图10所示,SMRwt-CPP胜肽以剂量依赖的方式抑制了全部细胞的生长,但阴性对照胜肽则否。发现观察到的抑制为剂量依赖的,具有剂量反应的典型S形形状,从而证实了观察的有效性。生长曲线进一步关于提供SMRwt-CPP对50%抑制(IC50)的特定剂量,其中MCF-7的IC50为180nM/mL(图10,图表A)、MDA-MB-231的IC50为476nM/mL(图10,图表B)、以及相对于K562的浓度为907nM/mL(图10,图表D)。非致瘤MCF-10A乳细胞作为负细胞对照,不受SMRwt-CPP影响(图10,图表C)。
实施例9:SMRwt胜肽及致死蛋白抑制剂在乳癌及白血病细胞株中阻挡胞外体释放
先前已显示PEG-SMRwt-Clu胜肽可在乳癌细胞中阻挡胞外体释放(Huang et al,Oncotarget(2017)8(7):p.11302-11315)。为了进一步检查阻挡胞外体释放的潜在机制,扩展了研究范围以检查SMRwt胜肽、PEG-SMRwt-Clu胜肽及SMRwt-CPP胜肽与致死蛋白抑制剂MKT-077、奥美拉唑及DMA对胞外体的释放影响。特别是,进行了乙酰胆碱酯酶(AchE)分析、NanoSight分析及西方墨点法分析,以确定自MCF-7及MDA-MB-231人类乳癌细胞与K562白血病细胞释放的胞外体的表征。如图11所示,将细胞在37℃下用各种胜肽及致死蛋白抑制剂处理5天。图表A、B及C描绘了通过乙酰胆碱酯酶(AchE)试验测量在以下细胞中释放的胞外体作为时间函数的相对数目:MCF-7乳癌细胞(图11,图表A);MDA-MB-231乳癌细胞(图11,图表B);及K562白血病细胞(图11,图表C)。
分析结果显示,SMRwt胜肽、PEG-SMRwt-Clu胜肽(SEQ ID NO:37)及SMRwt-CPP胜肽(SEQ ID NO:39)与致死蛋白抑制剂MKT-077、奥美拉唑及DMA皆于整个五天的治疗期内减少了外泌体释放的数量。如图11的图表A-C所示,在全部处理条件下,虽然在用SMRwt胜肽或致死蛋白抑制剂处理的细胞中初始提升及随后减少实际上为减少了,第1天及/或第2天的胞外体释放皆有初始提升,接着胞外体释放随后减少。特别是,用阴性对照(即,空载体、PEG-SMRmut-Clu(SEQ ID NO:43)及SMRmut-CPP(SEQ ID NO:41))处理的MCF-7细胞中AchE浓度分别为155.13mU/mL、151.5mU/mL及150.06mU/mL。这些处理条件(69.15mU/mL、69.0mU/mL及66.05mU/mL)于第3天时观察到急速减少,AChE浓度随后于第4天及第5天增加。
反之,发现使用PEG-SMRwt-Clu(SEQ ID NO:37)、SMRwt-CPP(SEQ ID NO:39)、MKT-077、奥美拉唑及DMA处理的MCF-7细胞于第1天至第5天均显示出减少的AChE浓度,其中平均AChE浓度分别为31mU/mL、22mU/mL、22mU/mL、26mU/mL及26mU/mL。
图11的图表B显示在MDA-MB-231乳癌细胞中相似治疗获得的结果。在此情况下,第1天观察到空载体、PEG-SMRmut-Clu及SMRmut-CPP处理下,分别初始提升AChE为146.52mU/mL、146.79mU/mL及141.47mU/mL,而后在第2-5天降低AChE浓度。然而,在使用PEG-SMRwt-Clu、SMRwt-CPP、MKT-077、奥美拉唑及DMA处理的MDA-MB-231细胞中,AChE水平于第1天至第5天维持在平均浓度水平分别为42mU/mL、29mU/mL、29mU/mL、25mU/mL及37mU/mL。
图11的图表C显示在K562白血病细胞中相似治疗获得的结果。在此情况下,阴性对照自第1天至第5天的平均AChE水平分别为48mU/mL、71mU/mL、75mU/mL、69mU/mL及59mU/mL。相较下,在使用PEG-SMRwt-Clu、SMRwt-CPP、MKT-077、奥美拉唑及DMA处理的K562细胞中,于第1-3天及第5天的平均AChE水平为18mU/mL、25mU/mL、21mU/mL及18mU/mL,在第4天显示出相对于其他几天有提升(即,41mU/mL)。这些结果进一步证实了全部的实验处理均抑制了胞外体释放(图11)。
实施例10:SMRwt胜肽及致死蛋白抑制剂对胞外体蛋白含量的影响
西方墨点法分析用于检查SMRwt胜肽、PEG-SMRwt-Clu胜肽及SMRwt-CPP胜肽与致死蛋白抑制剂MKT-077、奥美拉唑及DMA对于MCF-7、MDA-MB-231及K562细胞的胞外体蛋白质含量的影响。阴性对照处理包括PEG-SMRmut-Clu胜肽及SMRmut-CPP胜肽。自全部经处理及未经处理的细胞株中分离出胞外体。进行西方墨点法分析以评估MCF-7乳癌细胞(图12,图表A,左边亚图表)、MDA-MB-231乳癌细胞(图12,图表A,中间亚图表)及K562白血病细胞(图12,图表A,右边亚图表)中的胞外体蛋白质、Alix、致死蛋白及波形蛋白的表达水平。
如图12的图表A的左边亚图表及图12的图表B的左上亚图表所示,在PEG-SMRwt-CLU、SMRwt-CPP及MKT-077处理下,MCF-7细胞胞外体的Alix表现显著下降。然而,如图12的图表B的左上亚图表所示,使用奥美拉唑或DMA处理MCF-7细胞并没有伴随Alix表现的显著下降。相对于阴性对照(PEG-SMRmut-Clu及SMRmut-CPP),对于全部的处理(PEG-SMRwt-Clu、SMRwt-CPP、MKT-077、奥美拉唑及DMA),MCF-7细胞胞外体中波形蛋白的表现皆显著下降(图12,图表B,中间左边亚图表)。MCF-7胞外体中致死蛋白表现仅在使用PEG-SMRwt-Clu胜肽或MKT-077处理后显著下降,然而,在随后的观察中,使用SMRwt-CPP、奥美拉唑或DMA处理未观察到致死蛋白表现的显著变化(图12,图表B,左下亚图表)。
在MDA-MB-231乳癌细胞中(图12,图表A,中上亚图表;以及图12,图表B,中上亚图表),于使用PEG-SMRwt-Clu及SMRwt-CPP处理的细胞中,发现MDA-MB-231胞外体中的Alix表现显著下降,然而,在用三种致死蛋白抑制剂处理后未观察到显著变化。在使用PEG-SMRwt-Clu、SMRwt-CPP及DMA处理后,波形蛋白表现显著下降,然而,在使用MKT-077或奥美拉唑处理后,未观察到显著变化(图12,图表B,中上亚图表)。在使用PEG-SMRwt-Clu及SMRwt-CPP处理后,致死蛋白表现显著下降,但在DMA处理后,其抑制程度较小(图12,图表B,中间底部亚图表)。使用MKT-077或奥美拉唑处理MDA-MB-231细胞后,未观察到显著变化。
在K562白血病细胞中(图12,图表A,右上亚图表;以及,图12,图表B,右上亚图表),使用PEG-SMRwt-Clu、SMRwt-CPP、MKT-077、奥美拉唑及DMA处理后,K562胞外体中Alix表现显著下降。反之,在使用MKT-077、奥美拉唑及DMA处理后,K562胞外体中波形蛋白的表现显著,但在使用任何野生型或突变型SMR胜肽处理后,波形蛋白表现均未观察到显著变化(图12,图表B,中间右亚图表)。使用PEG-SMRwt-Clu、SMRwt-CPP、MKT-077、奥美拉唑及DMA处理后,致死蛋白表现显著下降。综上,来自图11及图12的数据表示胞外体数目及胞外体蛋白质含量根据特定治疗而被不同地调节。
实施例11:致死蛋白抑制剂对紫杉醇及顺铂诱导的细胞凋亡的影响
检查了致死蛋白抑制剂药物(MKT-077、DMA及奥美拉唑)单独使用或与紫杉醇(或顺铂)结合使用的影响,以观察其对MBA-MD-231、MCF-7及K562细胞凋亡的影响。具体而言,使用300μM/mL的DMA、200μM/mL的奥美拉唑或根据不同细胞使用不同浓度的MKT-077(MDA-MB-231,925nM/mL;MCF-7,500nM/mL;K562细胞,337.5nM/mL)处理这些细胞48小时,各种处理为单独或与1.6μM/mL紫杉醇或2mg/mL顺铂结合使用,并通过TUNEL试验进行细胞凋亡检测(图13)。
结果显示,(i)与MDA-MB-231细胞和紫杉醇(21.14%)及顺铂(27.53%)培养相比,单独的MKT-077(52.13%)细胞凋亡降低(图13,图表A)。而且,与MCF-7细胞和顺铂(77.13%)培养相比,单独的MKT-077(90.1%)细胞凋亡降低(图13,图表B)。与K562细胞和顺铂(60.43%)培养相比,单独的MKT-077(82.7%)细胞凋亡减少(图13,图表C)。然而,和紫杉醇培养的MCF-7细胞和K562细胞上未观察到显著变化。(ii)与MDA-MB-231细胞和顺铂(23.03%)培养相比,单独使用DMA细胞凋亡降低(30.43%)(图13,图表A);与MCF-7细胞和与紫杉醇培养(9.43%)相比,单独的DMA(11.83%)细胞凋亡减少(图13,图表B);与K562细胞和紫杉醇(1.63%)及顺铂(11.7%)培养相比,单独的DMA(15.2%)细胞凋亡减少(图13,图表C)。和紫杉醇培养的MCF-7细胞及和顺铂培养的MCF-7细胞均未观察到显著变化。(iii)与MDA-MB-231细胞和奥美拉唑(15.33%)及顺铂(29.05%)培养相比,单独的奥美拉唑(3.0%)观察到细胞凋亡增加(图13,图表A);与MCF-7细胞和顺铂培养(29.05%)相比,单独的奥美拉唑(1.1%)细胞凋亡增加(图13,图表B);与K562细胞和顺铂(13.5%)培养相比,单独的奥美拉唑(6.1%)细胞凋亡增加(图13,图表C)。和紫杉醇培养的MCF-7细胞及K562细胞均未观察到显著变化,虽然奥美拉唑与两种药物结合使用观察到很小的协同作用。
实施例12:SMRwt胜肽阻挡致死蛋白驱动的补体依赖细胞毒性的胞外体释放
补体介导的细胞毒性是宿主消除肿瘤细胞的正常细胞机制。已证实致死蛋白/GRP75结合补体因子C9,并通过致死蛋白经由胞外体诱导的膜攻击复合物(MAC)的胞吐作用而对补体依赖细胞毒性产生抗性中起主要作用(Pilzer et al.,Inti.Immunol.,(2005)17(9):p.1239-1248)。因此,令人感兴趣的是,观察SMR胜肽驱动的致死蛋白螯合及功能破坏是否增加了细胞对补体诱导的细胞死亡的敏感性。因此,将MCF-7、MDA-MB-231及K562细胞分别用280nM的PEG-SMRwt-Clu胜肽或560nM的SMRwt-CPP胜肽在37℃下处理60分钟,然后在37℃下用1μg/mL抗CXCR4抗体及50pL正常人血清(NHS;作为补体的来源)或正常热失活(人类)血清(NIS)处理60分钟(图14)。PEG-SMRmut-Clu胜肽及SMRmut-CPP胜肽作为阴性对照。通过台酚蓝排除法测定染色(死)细胞的百分比,该百分比代表3次独立实验。
在功能性补体(NHS)的存在下,两种SMRwt胜肽均显著诱导肿瘤细胞死亡。更具体地,在使用PEG-SMRwt-Clu处理的MCF-7细胞中,细胞死亡自补体阴性条件下的2.1%(第4条)增加到补体阳性条件下的26%(第8条)(图14,图表A);相同地,在使用SMRwt-CPP处理的MCF-7细胞中,细胞死亡从补体阴性条件下的2.1%(第6条)增加到补体阳性条件下的29%(第10条)(图14,图表A)。当使用SMRmutant胜肽处理时,这些作用于补体存在下被消除(第9、11条)(图14,图表A)。
在使用PEG-SMRwt-Clu处理的MDA-MB-231细胞中,细胞死亡从补体阴性条件下的3.6%(第4条)增加到补体阳性条件下的76%(第8条)(图14,图表B);相同地,在使用SMRwt-CPP处理的MDA-MB-231细胞中,细胞死亡从补体阴性条件下的3.6%(第6条)增加到补体阳性条件下的9%(第10条)(图14,图表B)。当使用SMRmutant胜肽处理时,这些作用于补体存在下被消除(第9、11条)(图14,图表B)。
在使用PEG-SMRwt-Clu处理的K562细胞中,细胞死亡从补体阴性条件下的4.3%(第4条)增加到补体阳性条件下的55%(第8条)(图14,图表C区;相同地,在使用SMRwt-CPP处理的K562细胞中,细胞死亡从补体阴性条件下的4.3%(第6条)增加到补体阳性条件下的23%(第10条)(图14,图表C)。当使用SMRmutant胜肽处理时,这些作用于补体存在下被消除(第9、11条)(图14,图表C)。
综上所述,这些数据显示,SMR诱导的致死蛋白螯合及功能破坏与补体介导的敏感性及细胞死亡有关。具体而言,阻挡致死蛋白功能可导致或增强肿瘤细胞对补体介导的细胞毒性的敏感性。
实施例13:致死蛋白小干扰RNA(siRNA)减少胞外体分泌及诱导补体介导的细胞毒性
siRNA剔除致死蛋白表现被用来进一步评估致死蛋白在减少胞外体分泌及保护肿瘤细胞免受补体介导的细胞毒性的作用。简言之,将MCF-7、MDA-MB-231及K562细胞在无胞外体的培养基中于37℃培养24小时。然后将细胞用表现双链致死蛋白siRNA的载体转染(Shelton et al,JVirol(2012)86(1):p.406-19;Huang et al,Oncotarget(2017)8(7):p.11302-11315)。阴性对照细胞用表现预计不会标靶任何已知脊椎动物基因的双链siRNA的载体进行转染。
使用抗致死蛋白及抗α-微管蛋白(内部对照)抗体通过SDS-PAGE/西方墨点法分析来测量细胞中的致死蛋白(图15,图表A)。通过相对条带强度的密度分析得到西方墨点法的定量结果(图15,图表B)。与使用阴性对照转染的细胞中的致死蛋白表现水平相比,标靶致死蛋白的siRNA的转染在细胞中的致死蛋白表现水平:对MCF-7为21.86%(图15,图表B,左亚图表)、对MDA-MB-231为6.28%(图15,图表B,中间亚图表)及对K562为35.3%(图15,图表C,右亚图表)。
此外,自细胞培养上清液中分离出胞外体,并通过NanoSight LM10奈米颗粒追踪分析(NTA)分析浓度及尺寸分布。使用NTA,可以根据布朗运动及相关扩散系数自动追踪及调整粒子尺寸。在通过NTA分析样品之前,已确定来自PBS的盐聚集体不会影响背景值,且设备中没有污染物颗粒。
该分析的结果显示于图15的图表C。在使用siRNA-Neg对照处理的MCF-7细胞中,发现细胞培养上清液含有3.91x109颗粒/mL,而用致死蛋白siRNA处理的细胞则含有5.79x108颗粒/mL(p<2.02E-07)(图15,图表C,左亚图表)。在使用siRNA-Neg对照处理的MDA-MB-231细胞中,发现细胞培养上清液含有5.71x109颗粒/ml,而经致死蛋白siRNA处理的细胞含有3.46x 109颗粒/mL(p<1.82E-06)(图15,图表C,中间亚图表)。在使用siRNA-Neg对照处理的K562细胞中,发现细胞培养上清液包括3.44x109颗粒/mL,而用致死蛋白siRNA处理的细胞包括2.58x108颗粒/mL(p<2.49E-06)(图15,图表C,右亚图表)。在全部三种培养中,NTA估计胞外体的尺寸在30到47nm的间(数据未显示)。
为了进一步验证致死蛋白中和作用使得肿瘤细胞对补体介导的细胞毒性产生敏感性或增强其敏感性,将MCF-7、MDA-MB-231及K562细胞用表现致死蛋白siRNA或阴性对照siRNA的载体转染,并在37℃下培养72小时。在4℃下用抗CXCR4抗体处理30分钟,然后在37℃下与NHS或NIS培养60分钟。来自这些实验的数据显示,相对于MCF-7细胞中的阴性对照,不表现致死蛋白导致致死蛋白介导的细胞免受补体依赖细胞毒性的保护为38.02%(图15,图表D,左边亚图表)、相对于MDA-MB-231细胞中的阴性对照为40.55%(图15,图表D,中间亚图表)、相对于K562细胞中的阴性对照为30.54%(图15,图表D,右边亚图表)。
实施例14:PEG-SMRwt-CLU胜肽影响MCF-7及MDA-MB-231乳癌细胞迁徙,但对非致瘤MCF-10A细胞则否
细胞迁徙或侵袭是癌症进展及转移的致命步骤,占所有人类癌症死亡率的90%。此外,细胞迁徙对于许多生物学学科(包括伤口愈合、炎症、细胞生长及分化)的各种不同病理学和生理学过程至关重要。细胞入侵指细胞在穿透细胞外基质(ECM)时发生的3维迁徙,且通常是与癌细胞转移相关的过程。为了进一步探讨该过程,确定SMRwt胜肽是否抑制乳癌细胞迁徙及侵袭为有意义的。因此,进行了迁徙试验以检查SMRwtg胜肽是否阻挡了肿瘤细胞的迁徙。
具体而言,对MDA-MB-231及MCF-7乳癌细胞使用1120nM的SMR胜肽(MCF-7细胞)、280nM的SMR胜肽(MDA-MB-231细胞)或3mM红海海绵蛋白A(阳性对照;已知的迁徙抑制剂)处理24小时后,根据制造商的说明(Calbiochem手册)进行细胞迁徙试验,使用设定激发波长为485nm、发射波长为515nm的荧光读盘仪。
在MCF-7细胞中,SMRwt-CPP胜肽、PEG-SMRwt-CLU胜肽及红海海绵蛋白A(正对照抑制剂)分别将迁徙减少了71.87%、75.74%及53.05%(图16A)。在MDA-MB-231细胞中,SMRwt-CPP胜肽、PEG-SMRwt-CLU胜肽及红海海绵蛋白A分别减少了46.39%、52.37%及50.39%的迁徙(图16B)。此外,该作用对于野生型SMR胜肽为特异性的,因为在用突变SMR胜肽处理后没有观察到明显的迁徙抑制。反之,在正常乳细胞株MCF-10A中,任何胜肽或抑制剂均未显著影响迁徙(图16C)。综上所述,这些数据显示,SMRwt-CPP及PEG-SMRwt-CLU胜肽可显著降低乳癌细胞的迁徙及侵袭,而突变的SMR胜肽则无统计学意义。
实施例15:实施例8-14的观察结果及结论摘要
通过添加细胞穿透胜肽(CPP)(一种衍生自HIV-1调节蛋白Tat的带正电荷的富含精胺酸的胜肽)、或凝聚素(CLU)胜肽(一种参与蛋白质分泌的分子伴侣)对HIV-1Nef蛋白的分泌修饰区(SMR)衍生的一系列胜肽进行修饰。在Nef SMR胜肽的C端添加CPP及CLU胜肽。还用聚乙二醇(PEG)修饰了CLU胜肽以增强溶解性。使用该胜肽处理细胞后,以MTT细胞存活率及迁徙分析来证实这些经修饰SMRwt胜肽对MDA-MB-231及MCF-7乳癌细胞及K562白血病细胞增殖的抑制作用。流式细胞仪用于确定补体介导的细胞凋亡及死亡。西方墨点法分析用于追踪胜肽介导的经处理细胞及经处理细胞所释放的胞外体中致死蛋白表现的变化。NanoSight分析及乙酰胆碱酯酶(AChE)分析用于测量培养基中的胞外体尺寸及胞外体浓度。
为了研究致死蛋白在乳癌及白血病细胞中的功能性作用,在MCF-7及MDA-MB-231乳癌细胞与白血病细胞中进行了致死蛋白的剔除实验,并进行了一系列测定以检验致死蛋白的表现及/或螯合对癌细胞的增殖及迁徙的影响。SMRwt胜肽与致死蛋白相互作用可显著减少细胞增殖并抑制癌细胞生长及细胞迁徙/侵袭。致死蛋白拥有的致癌功能似乎在乳癌及白血病细胞中都密切相关。尤其是,发现SMRwt胜肽会干扰致死蛋白促进及保护癌症进展的能力。首先,修饰的SMRwt胜肽减少了间质标记波形蛋白(VIM)的表现。第二,如通过迁徙测定所测量的,暴露于SMRwt胜肽抑制了乳癌细胞的迁徙。第三,SMRwt胜肽阻挡癌细胞释放胞外体的能力,继而阻挡胞外体介导的补体释放,从而在这些经胜肽处理的细胞中重新建立补体介导的细胞死亡。
本文的数据进一步显示:(i)SMRwt胜肽不仅有效地抑制了MDA-MB-231及MCF-7乳癌细胞生长,且无法预期地抑制了第二种无相关的肿瘤细胞株K562白血病细胞的生长;(ii)癌细胞中的致死蛋白-SMR胜肽相互作用显示出细胞凋亡增加,这与SMRwt胜肽干扰癌细胞对补体依赖细胞毒性的抗性一致;(i ii)siRNA介导的致死蛋白剔除减少了膜攻击复合物(MAC)的消除,并增强了细胞对MAC诱导的细胞死亡的敏感性;(iv)SMRwt胜肽及致死蛋白抑制剂MKT-077、奥美拉唑及5-(N,N-二甲基)阿米洛利(DMA)阻挡了MCF-7及MDA-MB-231乳癌细胞与K562白血病细胞的胞外体分泌;以及,(v)PEG-SMRwt胜肽通过阻挡胞外体释放来抑制MCF-7及MDA-MB-231乳癌细胞迁徙。
总而言之,数据表示,致死蛋白通过诱导上皮间质转化(EMT),例如在白血病细胞中,促进细胞增殖、侵袭及抵抗补体介导的细胞死亡。SMRwt胜肽拮抗致死蛋白的功能,阻挡肿瘤胞外体释放及胞外体介导的补体释放,并拮抗与EMT相关的肿瘤细胞迁徙及侵袭。单独使用这些胜肽或与其他活性剂结合治疗癌细胞可减少乳癌及/或白血病细胞的侵袭及迁徙,并有助于这些晚期肿瘤细胞的标准治疗。本文介绍的发现具有重要的临床意义,并支持进一步研究SMR胜肽对癌症的治疗价值。
以上描述的目的在于教导本领域技术人员如何实施本说明书,并非旨在详细描述对阅读了本说明书后的技术人员显而易见的全部这些明显修改及变化。然而,全部这些明显的修改及变化均包括在本实施方案的范围内,该范围由后附申请专利范围限定。除非上下文有明确相反的指示,否则申请专利范围旨在保护有效地达到预期目标的所请的组分及任何顺序的步骤。
<110> 莫尔豪斯医学院
<120> 用于通过抑制胞外体释放以治疗疾病的组成物及方法
<130> 1013-364 CIP
<140> xx/xxx,xxx
<141> 20xx-xx-xx
<150> 16/030,430
<151> 2018-07-09
<150> 15/383,454
<151> 2016-12-19
<160> 35
<170> PatentIn version 3.5
<210> 1
<211> 5
<212> PRT
<213> 人工序列
<220>
<221>
<223> 合成的
<400> 1
Val Gly Phe Pro Val
1 5
<210> 2
<211> 12
<212> PRT
<213> 人工序列
<220>
<221>
<223> 合成的
<400> 2
Val Gly Phe Pro Val Ala Ala Val Gly Phe Pro Val
1 5 10
<210> 3
<211> 12
<212> PRT
<213> 人工序列
<220>
<221>
<223> 合成的
<400> 3
His Pro Leu Ser Lys His Pro Tyr Trp Ser Gln Pro
1 5 10
<210> 4
<211> 12
<212> PRT
<213> 人工序列
<220>
<221>
<223> 合成的
<400> 4
Asn Thr Tyr Trp Ser Gln Leu Leu His Phe Gln Thr
1 5 10
<210> 5
<211> 12
<212> PRT
<213> 人工序列
<220>
<221>
<223> 合成的
<400> 5
Ser His Ala Leu Pro Leu Thr Trp Ser Thr Ala Ala
1 5 10
<210> 6
<211> 24
<212> PRT
<213> 人工序列
<220>
<221>
<223> 合成的
<400> 6
Val Gly Phe Pro Val Ala Ala Val Gly Phe Pro Val His Pro Leu Ser
1 5 10 15
Lys His Pro Tyr Trp Ser Gln Pro
20
<210> 7
<211> 26
<212> PRT
<213> 人工序列
<220>
<221>
<223> 合成的
<400> 7
Val Gly Phe Pro Val Ala Ala Val Gly Phe Pro Val Ala Ala His Pro
1 5 10 15
Leu Ser Lys His Pro Tyr Trp Ser Gln Pro
20 25
<210> 8
<211> 40
<212> PRT
<213> 人工序列
<220>
<221>
<223> 合成的
<400> 8
Val Gly Phe Pro Val Ala Ala Val Gly Phe Pro Val Ala Ala His Pro
1 5 10 15
Leu Ser Lys His Pro Tyr Trp Ser Gln Pro Ala Ala His Pro Leu Ser
20 25 30
Lys His Pro Tyr Trp Ser Gln Pro
35 40
<210> 9
<211> 29
<212> PRT
<213> 人工序列
<220>
<221>
<223> 合成的
<400> 9
Met Ser Val Leu Thr Pro Leu Leu Leu Arg Gly Leu Thr Gly Ser Ala
1 5 10 15
Arg Arg Leu Pro Val Pro Arg Ala Lys Ile His Ser Leu
20 25
<210> 10
<211> 33
<212> PRT
<213> 人工序列
<220>
<221>
<223> 合成的
<400> 10
Met Leu Ser Asn Leu Arg Ile Leu Leu Asn Lys Ala Ala Leu Arg Lys
1 5 10 15
Ala His Thr Ser Met Val Arg Asn Phe Arg Tyr Gly Lys Pro Val Gln
20 25 30
Cys
<210> 11
<211> 18
<212> PRT
<213> 人工序列
<220>
<221>
<223> 合成的
<400> 11
Met Leu Ser Leu Arg Gln Ser Ile Arg Phe Phe Lys Pro Ala Thr Arg
1 5 10 15
Thr Leu
<210> 12
<211> 16
<212> PRT
<213> 人工序列
<220>
<221>
<223> 合成的
<400> 12
Arg Gln Ile Lys Ile Trp Phe Gln Asn Arg Arg Met Lys Trp Lys Lys
1 5 10 15
<210> 13
<211> 34
<212> PRT
<213> 人工序列
<220>
<221>
<223> 合成的
<400> 13
Met Phe Ser Tyr Leu Pro Arg Tyr Pro Leu Arg Ala Ala Ser Ala Arg
1 5 10 15
Ala Leu Val Arg Ala Thr Arg Pro Ser Tyr Arg Ser Ala Leu Leu Arg
20 25 30
Tyr Gln
<210> 14
<211> 20
<212> PRT
<213> 人工序列
<220>
<221>
<223> 合成的
<400> 14
Met Ala Ala Trp Met Arg Ser Leu Phe Ser Pro Leu Lys Lys Leu Trp
1 5 10 15
Ile Arg Met His
20
<210> 15
<211> 13
<212> PRT
<213> 人工序列
<220>
<221>
<223> 合成的
<400> 15
Met Lys Leu Leu Trp Arg Leu Ile Leu Ser Arg Lys Trp
1 5 10
<210> 16
<211> 14
<212> PRT
<213> 人工序列
<220>
<221>
<223> 合成的
<400> 16
Met Trp Trp Arg Arg Ser Arg Thr Asn Ser Leu Arg Tyr Thr
1 5 10
<210> 17
<211> 16
<212> PRT
<213> 人工序列
<220>
<221>
<223> 合成的
<400> 17
Met Leu Phe Arg Leu Arg Arg Ser Val Arg Leu Arg Gly Leu Leu Ala
1 5 10 15
<210> 18
<211> 20
<212> PRT
<213> 人工序列
<220>
<221>
<223> 合成的
<400> 18
Met Trp Thr Leu Gly Arg Arg Ala Val Ala Gly Leu Leu Ala Ser Pro
1 5 10 15
Ser Pro Ala Gln
20
<210> 19
<211> 20
<212> PRT
<213> 人工序列
<220>
<221>
<223> 合成的
<400> 19
Arg Arg Ile Val Val Leu His Gly Tyr Gly Ala Val Lys Glu Val Leu
1 5 10 15
Leu Asn His Lys
20
<210> 20
<211> 22
<212> PRT
<213> 人工序列
<220>
<221>
<223> 合成的
<400> 20
Met Leu Ser Leu Arg Gln Asp Ile Arg Phe Phe Lys Pro Ala Thr Arg
1 5 10 15
Thr Leu Cys Ser Ser Arg
20
<210> 21
<211> 8
<212> PRT
<213> 人工序列
<220>
<221>
<223> 合成的
<400> 21
Arg Pro Leu Ala Leu Trp Arg Ser
1 5
<210> 22
<211> 8
<212> PRT
<213> 人工序列
<220>
<221>
<223> 合成的
<400> 22
Glu Ser Pro Ala Tyr Tyr Thr Ala
1 5
<210> 23
<211> 6
<212> PRT
<213> 人工序列
<220>
<221>
<223> 合成的
<400> 23
Asp Pro Arg Ser Phe Leu
1 5
<210> 24
<211> 6
<212> PRT
<213> 人工序列
<220>
<221>
<223> 合成的
<400> 24
Pro Pro Arg Ser Phe Leu
1 5
<210> 25
<211> 6
<212> PRT
<213> 人工序列
<220>
<221>
<223> 合成的
<400> 25
Arg Leu Gln Leu Lys Leu
1 5
<210> 26
<211> 5
<212> PRT
<213> 人工序列
<220>
<221>
<223> 合成的
<220>
<221> MOD_RES
<222> (5)..(5)
<223> 乙酰化
<400> 26
Arg Leu Gln Leu Lys
1 5
<210> 27
<211> 4
<212> PRT
<213> 人工序列
<220>
<221>
<223> 合成的
<220>
<221> misc_feature
<222> (2)..(3)
<223> Xaa可为任何自然存在的胺基酸
<400> 27
Arg Xaa Xaa Arg
1
<210> 28
<211> 4
<212> PRT
<213> 人工序列
<220>
<221>
<223> 合成的
<220>
<221> misc_feature
<222> (2)..(2)
<223> Xaa可为任何自然存在的胺基酸
<220>
<221> misc_feature
<222> (3)..(3)
<223> Xaa为Lys或Arg
<400> 28
Arg Xaa Xaa Arg
1
<210> 29
<211> 4
<212> PRT
<213> 人工序列
<220>
<221>
<223> 合成的
<220>
<221> misc_feature
<222> (2)..(2)
<223> Xaa为Glu或Asp
<400> 29
Ile Xaa Gly Arg
1
<210> 30
<211> 6
<212> PRT
<213> 人工序列
<220>
<221>
<223> 合成的
<400> 30
Leu Val Pro Arg Gly Ser
1 5
<210> 31
<211> 13
<212> DNA
<213> 人工序列
<220>
<221>
<223> 合成的
<400> 31
ccgccaagaa gcg 13
<210> 32
<211> 100
<212> DNA
<213> 人工序列
<220>
<221>
<223> 合成的
<400> 32
gcgtgcacac gcgcgtagac ttcccccgca agtcactcgt tagcccgcca agaagcgacc 60
cctccggggc gagctgagcg gcgtggcgcg ggggcgtcat 100
<210> 33
<211> 101
<212> DNA
<213> 人工序列
<220>
<221>
<223> 合成的
<400> 33
acgtgcatac gcacgtagac attccccgct tcccactcca aagtccgcca agaagcgtat 60
cccgctgagc ggcgtggcgc gggggcgtca tccgtcagct c 101
<210> 34
<211> 58
<212> DNA
<213> 人工序列
<220>
<221>
<223> 合成的
<400> 34
acttcccccg caagtcactc gttagcccgc caagaagcga cccctccggg gcgagctg 58
<210> 35
<211> 20
<212> PRT
<213> 人工序列
<220>
<221>
<223> 合成的
<220>
<221> misc_feature
<222> (1)..(4)
<223> 可存在至少一个且至多四个
<220>
<221> misc_feature
<222> (5)..(5)
<223> Xaa为Ser或Ala
<220>
<221> misc_feature
<222> (6)..(20)
<223> 可存在或不存在"Gly(1-4)-Ser/Ala"
<400> 35
Gly Gly Gly Gly Xaa Gly Gly Gly Gly Xaa Gly Gly Gly Gly Xaa Gly
1 5 10 15
Gly Gly Gly Xaa
20
<210> 36
<211> 15
<212> PRT
<213> 人工序列
<220>
<221>
<223> 合成的
<400> 36
Asn Xaa Asn Val Gly Phe Pro Val Ala Ala Val Gly Phe Pro Val
1 5 10 15
<210> 37
<211> 27
<212> PRT
<213> 人工序列
<220>
<221>
<223> 合成的
<400> 37
Asn Xaa Asn Val Gly Phe Pro Val Ala Ala Val Gly Phe Pro Val His
1 5 10 15
Pro Leu Ser Lys His Pro Tyr Trp Ser Gln Pro
20 25
<210> 38
<211> 13
<212> PRT
<213> 人类免疫不全病毒(Human immunodeficiency virus)
<400> 38
Gly Arg Lys Lys Arg Arg Gln Arg Arg Arg Pro Pro Gln
1 5 10
<210> 39
<211> 25
<212> PRT
<213> 人工序列
<220>
<221>
<223> 合成的
<400> 39
Val Gly Phe Pro Val Ala Ala Val Gly Phe Pro Val Gly Arg Lys Lys
1 5 10 15
Arg Arg Gln Arg Arg Arg Pro Pro Gln
20 25
<210> 40
<211> 12
<212> PRT
<213> 人工序列
<220>
<221>
<223> 合成的
<400> 40
Ala Gly Phe Pro Val Ala Ala Ala Gly Phe Pro Val
1 5 10
<210> 41
<211> 25
<212> PRT
<213> 人工序列
<220>
<221>
<223> 合成的
<400> 41
Ala Gly Phe Pro Val Ala Ala Ala Gly Phe Pro Val Gly Arg Lys Lys
1 5 10 15
Arg Arg Gln Arg Arg Arg Pro Pro Gln
20 25
<210> 42
<211> 15
<212> PRT
<213> 人工序列
<220>
<221>
<223> 合成的
<400> 42
Asn Xaa Asn Ala Gly Phe Pro Val Ala Ala Ala Gly Phe Pro Val
1 5 10 15
<210> 43
<211> 27
<212> PRT
<213> 人工序列
<220>
<221>
<223> 合成的
<400> 43
Asn Xaa Asn Ala Gly Phe Pro Val Ala Ala Ala Gly Phe Pro Val His
1 5 10 15
Pro Leu Ser Lys His Pro Tyr Trp Ser Gln Pro
20 25
<210> 44
<211> 24
<212> PRT
<213> 人工序列
<220>
<221>
<223> 合成的
<400> 44
Ala Gly Phe Pro Val Ala Ala Ala Gly Phe Pro Val His Pro Leu Ser
1 5 10 15
Lys His Pro Tyr Trp Ser Gln Pro
20
<210> 45
<211> 17
<212> PRT
<213> 人工序列
<220>
<221>
<223> 合成的
<400> 45
Gly Gly Gly Gly His Leu Asn Ile Leu Ser Thr Leu Trp Lys Tyr Arg
1 5 10 15
Cys
<210> 46
<211> 20
<212> PRT
<213> 人工序列
<220>
<221>
<223> 合成的
<400> 46
Thr Phe Phe Tyr Gly Gly Ser Arg Gly Lys Arg Asn Asn Phe Lys Thr
1 5 10 15
Glu Glu Tyr Cys
20
<210> 47
<211> 8
<212> PRT
<213> 人工序列
<220>
<221>
<223> 合成的
<400> 47
Arg Arg Arg Arg Arg Arg Arg Arg
1 5
<210> 48
<211> 10
<212> PRT
<213> 人工序列
<220>
<221>
<223> 合成的
<400> 48
Leu Arg Lys Leu Arg Lys Arg Leu Leu Arg
1 5 10
<210> 49
<211> 14
<212> PRT
<213> 人工序列
<220>
<221>
<223> 合成的
<400> 49
Cys Gly His Lys Ala Lys Gly Pro Arg Lys Gly Lys Arg Lys
1 5 10
<210> 50
<211> 16
<212> PRT
<213> 人工序列
<220>
<221>
<223> 合成的
<400> 50
Phe Lys Glu Ser Trp Arg Glu Ala Arg Gly Thr Arg Ile Glu Arg Gly
1 5 10 15
<210> 51
<211> 17
<212> PRT
<213> 人工序列
<220>
<221>
<223> 合成的
<400> 51
Lys Ser Val Arg Thr Trp Asn Glu Ile Ile Pro Ser Lys Gly Cys Leu
1 5 10 15
Arg
<210> 52
<211> 7
<212> PRT
<213> 人工序列
<220>
<221>
<223> 合成的
<400> 52
His Ala Ile Tyr Pro Arg His
1 5
<210> 53
<211> 12
<212> PRT
<213> 人工序列
<220>
<221>
<223> 合成的
<400> 53
Thr Gly Asn Tyr Lys Ala Leu His Pro His Asn Gly
1 5 10
<210> 54
<211> 12
<212> PRT
<213> 人工序列
<220>
<221>
<223> 合成的
<400> 54
Thr His Arg Pro Pro Met Trp Ser Pro Val Trp Pro
1 5 10
<210> 55
<211> 29
<212> PRT
<213> 人工序列
<220>
<221>
<223> 合成的
<400> 55
Tyr Thr Ile Trp Met Pro Glu Asn Pro Arg Pro Gly Thr Pro Cys Asp
1 5 10 15
Ile Phe Thr Asn Ser Arg Gly Lys Arg Ala Ser Asn Gly
20 25
权利要求书(按照条约第19条的修改)
1.一种治疗癌症的方法,包括:
对有需要该治疗的个体投予有效量的医药组成物,其中该医药组成物是包括具有多部分胜肽的抗癌剂,该多部分胜肽具有至少一个来自HIV-1Nef的分泌修饰区(SMR)胜肽,且该SMR胜肽与至少一个细胞穿透胜肽(CPP)及至少一个凝聚素(Clusterin,Clu)结合胜肽(Clu-BP)融合,
其中,该SMR胜肽包括选自由以下组成的群组的胺基酸序列:VGFPV(SEQ ID NO:1)、VGFPVAAVGFPV(SEQ ID NO:2)、VGFPVAAVGFPVHPLSKHPYWSQP(SEQ ID NO:6)、VGFPVAAVGFPVAAHPLSKHPYWSQP(SEQ ID NO:7)、VGFPVAAVGFPVAAHPLSKHPYWSQPAAHPLSKHPYWSQP(SEQ ID NO:8)、NXNVGFPVAAVGFPV(SEQ ID NO:36)、NXNVGFPVAAVGFPVHPLSKHPYWSQP(SEQ ID NO:37),及
其中,该至少一个Clu-BP是包括选自由以下组成的群组的胺基酸序列:HPLSKHPYWSQP(SEQ ID NO:3)、NTYWSQLLHFQT(SEQ ID NO:4)、及SHALPLTWSTAA(SEQ ID NO:5)。
2.如权利要求1的方法,其特征在于,该至少一个CPP是包括SEQ ID NO:38的胺基酸序列。
3.如权利要求1的方法,其特征在于,该多部分胜肽为聚乙二醇化的。
4.如权利要求1的方法,其特征在于,该个体具有乳癌。
5.如权利要求1的方法,其特征在于,该个体具有白血病。
6.如权利要求1的方法,进一步包括对该个体投予第二抗癌剂的步骤。
7.如权利要求10的方法,其特征在于,该第二抗癌剂为紫杉醇(paclitaxel)或顺铂(cisplatin)。
8.如权利要求6的方法,其特征在于,该第二抗癌剂为致死蛋白(mortalin)抑制剂。
9.如权利要求12的方法,其特征在于,该致死蛋白抑制剂为MKT-077、奥美拉唑、或5-(N,N-二甲基)阿米洛利(5-(N,N-dimethyl)amiloride,DMA)。
10.一种多核苷酸,其编码权利要求1的多部分胜肽(multipartite peptide)。
11.一种表现载体,其包括可操控地连接至调节序列的如权利要求7的多核苷酸。
12.一种细胞,其包括如权利要求15的表现载体。
13.一种医药组成物,其包括如权利要求1的多部分胜肽及医药上可接受载剂。
14.如权利要求17的医药组成物,其进一步包括第二抗癌剂。
15.如权利要求18的医药组成物,其特征在于,该第二抗癌剂选自由以下组成的群组:致死蛋白(Hsp70)抑制剂、烷化剂、蒽环抗生素、抗代谢物、解毒剂、干扰素、多株(polyclonal)或单株抗体、EGFR抑制剂、HER2抑制剂、组蛋白去乙酰酶抑制剂、荷尔蒙或抗荷尔蒙剂、有丝分裂抑制剂、磷脂酰肌醇3-激酶(PI3K)抑制剂、Akt抑制剂、哺乳动物标靶的雷帕霉素(mTOR)抑制剂、蛋白酶体抑制剂、聚(ADP-核糖)聚合酶(PARP)抑制剂、Ras/MAPK路径抑制剂、中心体解簇剂(centrosome declustering agent)、多激酶抑制剂、丝胺酸/苏胺酸激酶抑制剂、酪胺酸激酶抑制剂、VEGF/VEGFR抑制剂、紫杉烷或紫杉烷衍生物、芳香酶抑制剂、蒽环类药物、微管标靶药物、拓朴异构酶毒药、及前述的组合。
16.如权利要求17的医药组成物,其特征在于,该多部分胜肽为聚乙二醇化的。
17.如权利要求17的医药组成物,其特征在于,该多部分胜肽并入奈米颗粒中、并于奈米颗粒上、或者与奈米颗粒连结。
Claims (21)
1.一种治疗癌症的方法,包括:
对有需要该治疗的个体投予有效量的医药组成物,其中该医药组成物是包括具有至少一个来自HIV-1 Nef的分泌修饰区(SMR)胜肽的抗癌剂,且该SMR胜肽与至少一个细胞穿透胜肽(CPP)或至少一个凝聚素(Clusterin,Clu)结合胜肽(Clu-BP)融合。
2.如权利要求1的方法,其特征在于,该SMR胜肽与至少一个CPP融合。
3.如权利要求1的方法,其特征在于,该SMR胜肽与至少一个Clu-BP融合。
4.如权利要求1的方法,其特征在于,该SMR胜肽包括选自由以下组成的群组的胺基酸序列:VGFPV(SEQ ID NO: 1)、VGFPVAAVGFPV(SEQ ID NO: 2)、VGFPVAAVGFPVHPLSKHPYWSQP(SEQ ID NO: 6)、VGFPVAAVGFPVAAHPLSKHPYWSQP(SEQ ID NO: 7)、VGFPVAAVGFPVAAHPLSKHPYWSQPAAHPLSKHPYWSQP(SEQ ID NO: 8)、NXNVGFPVAAVGFPV(SEQ ID NO: 36)、NXNVGFPVAAVGFPVHPLSKHPYWSQP(SEQ ID NO: 37)、及GRKKRRQRRRPPQ(SEQ ID NO: 39)。
5.如权利要求2的方法,其特征在于,该至少一个CPP是包括SEQ ID NO: 38的胺基酸序列。
6.如权利要求3的方法,其特征在于,该至少一个Clu-BP是包括选自由以下组成的群组的胺基酸序列:HPLSKHPYWSQP(SEQ ID NO: 3)、NTYWSQLLHFQT(SEQ ID NO: 4)、及SHALPLTWSTAA(SEQ ID NO: 5)。
7.如权利要求1的方法,其特征在于,该医药组成物进一步包括至少一个。
8.如权利要求1的方法,其特征在于,该个体具有乳癌。
9.如权利要求1的方法,其特征在于,该个体具有白血病。
10.如权利要求1的方法,进一步包括对该个体投予第二抗癌剂的步骤。
11.如权利要求10的方法,其特征在于,该第二抗癌剂为紫杉醇(paclitaxel)或顺铂(cisplatin)。
12.如权利要求6的方法,其特征在于,该第二抗癌剂为致死蛋白(mortalin)抑制剂。
13.如权利要求12的方法,其特征在于,该致死蛋白抑制剂为MKT-077、奥美拉唑、或5-(N,N-二甲基)阿米洛利(5-(N,N-dimethyl)amiloride,DMA)。
14.一种多核苷酸,其编码权利要求1的多部分胜肽(multipartite peptide)。
15.一种表现载体,其包括可操控地连接至调节序列的如权利要求7的多核苷酸。
16.一种细胞,其包括如权利要求15的表现载体。
17.一种医药组成物,其包括如权利要求1的多部分胜肽及医药上可接受载剂。
18.如权利要求17的医药组成物,其进一步包括第二抗癌剂。
19.如权利要求18的医药组成物,其特征在于,该第二抗癌剂选自由以下组成的群组:致死蛋白(Hsp70)抑制剂、烷化剂、蒽环抗生素、抗代谢物、解毒剂、干扰素、多株(polyclonal)或单株抗体、EGFR抑制剂、HER2抑制剂、组蛋白去乙酰酶抑制剂、荷尔蒙或抗荷尔蒙剂、有丝分裂抑制剂、磷脂酰肌醇3-激酶(PI3K)抑制剂、Akt抑制剂、哺乳动物标靶的雷帕霉素(mTOR)抑制剂、蛋白酶体抑制剂、聚(ADP-核糖)聚合酶(PARP)抑制剂、Ras/MAPK路径抑制剂、中心体解簇剂(centrosome declustering agent)、多激酶抑制剂、丝胺酸/苏胺酸激酶抑制剂、酪胺酸激酶抑制剂、VEGF/VEGFR抑制剂、紫杉烷或紫杉烷衍生物、芳香酶抑制剂、蒽环类药物、微管标靶药物、拓朴异构酶毒药、及前述的组合。
20.如权利要求17的医药组成物,其特征在于,该多部分胜肽为聚乙二醇化的。
21.如权利要求17的医药组成物,其特征在于,该多部分胜肽并入奈米颗粒中、并于奈米颗粒上、或者与奈米颗粒连接。
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US15/383,454 US10040831B2 (en) | 2016-12-19 | 2016-12-19 | Compositions and methods for treating diseases by inhibiting exosome release |
US16/030,430 US10544193B2 (en) | 2016-12-19 | 2018-07-09 | Compositions and methods for treating diseases by inhibiting exosome release |
US16/030,430 | 2018-07-09 | ||
PCT/US2018/066567 WO2020013879A1 (en) | 2016-12-19 | 2018-12-19 | Compositions and methods for treating diseases by inhibiting exosome release |
Publications (2)
Publication Number | Publication Date |
---|---|
CN112823025A true CN112823025A (zh) | 2021-05-18 |
CN112823025B CN112823025B (zh) | 2023-12-08 |
Family
ID=62557202
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201680092090.9A Active CN110312549B (zh) | 2016-12-19 | 2016-12-19 | 用于通过抑制外泌体释放来治疗疾病的组合物和方法 |
CN201880097355.3A Active CN112823025B (zh) | 2016-12-19 | 2018-12-19 | 用于通过抑制胞外体释放以治疗疾病的组成物及方法 |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201680092090.9A Active CN110312549B (zh) | 2016-12-19 | 2016-12-19 | 用于通过抑制外泌体释放来治疗疾病的组合物和方法 |
Country Status (4)
Country | Link |
---|---|
US (2) | US10040831B2 (zh) |
EP (2) | EP3554638B1 (zh) |
CN (2) | CN110312549B (zh) |
WO (2) | WO2018118015A1 (zh) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN113995848A (zh) * | 2021-09-29 | 2022-02-01 | 吉林大学 | 一种金纳米棒复合材料及其制备方法与应用 |
CN116970574A (zh) * | 2023-06-26 | 2023-10-31 | 广东省农业科学院动物卫生研究所 | 一种鹅源波形蛋白的用途、促进增殖鹅星状病毒的方法及用途、疫苗 |
Families Citing this family (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10800817B2 (en) | 2016-12-19 | 2020-10-13 | Morehouse School Of Medicine | Compositions and methods for treating diseases by inhibiting exosome release |
WO2018118015A1 (en) * | 2016-12-19 | 2018-06-28 | Morehouse School Of Medicine | Compositions and methods for treating diseases by inhibiting exosome release |
JP7356450B2 (ja) * | 2018-01-05 | 2023-10-04 | サイブレクサ 1・インコーポレイテッド | 酸性または低酸素の疾患組織を含む疾患の治療のための化合物、組成物、及び方法 |
CN112543595B (zh) * | 2018-05-30 | 2022-11-01 | 莫尔豪斯医学院 | 抗微生物组合物,其制备方法和用途 |
CN111579785B (zh) * | 2020-04-29 | 2022-09-13 | 南方医科大学深圳医院 | 一种基于血浆外泌体蛋白的hpv感染致宫颈癌的早期诊断标志物及其应用 |
CN113082221B (zh) * | 2021-04-29 | 2022-05-31 | 中国人民解放军陆军特色医学中心 | Tyr/Ang双重修饰的青蒿琥酯纳米靶向制剂的制备方法和在颅脑肿瘤治疗中的应用 |
US11180534B1 (en) | 2021-06-04 | 2021-11-23 | Morehouse School Of Medicine | Compositions and methods for treating SARS-CoV-2 infections |
Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20120121507A1 (en) * | 2009-04-17 | 2012-05-17 | Rana Filfil | Peptide ligands for clusterin and uses thereof |
WO2013052058A1 (en) * | 2011-10-07 | 2013-04-11 | Morehouse School Of Medicine | Antimicrobial compositions and methods of use thereof |
US20130089525A1 (en) * | 2011-10-07 | 2013-04-11 | Morehouse School Of Medicine | Antimicrobial compositions and methods of use thereof |
CN103096932A (zh) * | 2010-06-14 | 2013-05-08 | 弗·哈夫曼-拉罗切有限公司 | 细胞穿透肽及其用途 |
US20170369533A1 (en) * | 2011-12-15 | 2017-12-28 | Morehouse School Of Medicine | Compositions and methods for exosome targeted expression |
US20180140661A1 (en) * | 2016-11-18 | 2018-05-24 | City Of Hope | Peptide inhibitors of twist |
US20180170969A1 (en) * | 2016-12-19 | 2018-06-21 | Morehouse School Of Medicine | Compositions and methods for treating diseases by inhibiting exosome release |
Family Cites Families (31)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4631190A (en) | 1981-06-26 | 1986-12-23 | Shen Wei C | Acidity-sensitive spacer molecule to control the release of pharmaceuticals from molecular carriers |
US4542225A (en) | 1984-08-29 | 1985-09-17 | Dana-Farber Cancer Institute, Inc. | Acid-cleavable compound |
NZ238473A (en) | 1990-06-19 | 1993-11-25 | Keith James Ross | Lever lock having levers protected by an internal lever housing |
US5252714A (en) | 1990-11-28 | 1993-10-12 | The University Of Alabama In Huntsville | Preparation and use of polyethylene glycol propionaldehyde |
JPH04334377A (ja) | 1990-12-31 | 1992-11-20 | Akzo Nv | 酸−不安定性リンカー分子 |
US5556623A (en) | 1993-03-30 | 1996-09-17 | Eli Lilly And Company | Antibody-drug conjugates |
US5569754A (en) | 1993-06-11 | 1996-10-29 | Board Of Regents, University Of Tx Systems | RNA import elements for transport into mitochondria |
US5672662A (en) | 1995-07-07 | 1997-09-30 | Shearwater Polymers, Inc. | Poly(ethylene glycol) and related polymers monosubstituted with propionic or butanoic acids and functional derivatives thereof for biotechnical applications |
US5897945A (en) | 1996-02-26 | 1999-04-27 | President And Fellows Of Harvard College | Metal oxide nanorods |
US6506564B1 (en) | 1996-07-29 | 2003-01-14 | Nanosphere, Inc. | Nanoparticles having oligonucleotides attached thereto and uses therefor |
US5990237A (en) | 1997-05-21 | 1999-11-23 | Shearwater Polymers, Inc. | Poly(ethylene glycol) aldehyde hydrates and related polymers and applications in modifying amines |
FR2766205B1 (fr) | 1997-07-16 | 2002-08-30 | Inst Nat Sante Rech Med | Nouveau procede de sensibilisation de cellules presentatrices d'antigene et nouveaux moyens pour la mise en oeuvre du procede |
US5985263A (en) | 1997-12-19 | 1999-11-16 | Enzon, Inc. | Substantially pure histidine-linked protein polymer conjugates |
AU2002330938A1 (en) | 2001-07-31 | 2003-02-17 | Northeastern University | Mitochondrial genome replenishment |
CN1863508A (zh) * | 2003-08-01 | 2006-11-15 | 独立行政法人产业技术综合研究所 | 具有糖链的靶向性和肠道吸收控制性脂质体以及含有该脂质体的癌症治疗药和诊断药 |
CN1839799B (zh) * | 2006-01-18 | 2010-05-12 | 复旦大学 | 一种凝集素修饰的经鼻入脑的药物传递系统 |
WO2008054544A2 (en) | 2006-05-22 | 2008-05-08 | Immune Disease Institute, Inc. | Method for delivery across the blood brain barrier |
KR20100074177A (ko) | 2007-09-10 | 2010-07-01 | 유니버시티 오브 매사추세츠 | 미토콘드리아-표적화된 항-종양 물질 |
FR2937322B1 (fr) | 2008-10-22 | 2013-02-22 | Vect Horus | Derives peptidiques et leur utilisation comme vecteurs de molecules sous forme de conjugues |
US8431530B2 (en) * | 2009-06-12 | 2013-04-30 | Morehouse School Of Medicine | Compositions and methods for treating aids or cancer by inhibiting the secretion of microparticles |
IN2012DN00248A (zh) | 2009-07-02 | 2015-05-01 | Angiochem Inc | |
KR101906146B1 (ko) | 2009-08-17 | 2018-10-10 | 메모리얼 슬로안-케터링 캔서 센터 | 열 충격 단백질 결합 화합물, 조성물, 및 이의 제조 방법 및 사용 방법 |
EP2516462B1 (en) | 2009-12-23 | 2015-05-06 | Avipep Pty Ltd | Immuno-conjugates and methods for producing them |
FR2959229B1 (fr) | 2010-04-21 | 2013-01-18 | Vect Horus | Derives peptidiques, leur preparation et leurs utilisations |
EP2750686B1 (en) | 2011-06-17 | 2017-06-14 | Shire Human Genetic Therapies, Inc. | Polypeptide comprising frataxin and a c-terminal mitochondria penetrating peptide for use in the treatment of friedreich's ataxia |
US20140196172A1 (en) | 2011-08-04 | 2014-07-10 | Her Majesty The Queen In Right Of Canada, As Repre Sented By The Minister Of Agriculture And Agrifoo | Organelle Targeting Nanocarriers |
US9642843B2 (en) | 2013-02-27 | 2017-05-09 | The Regents Of The University Of Michigan | Pharmaceutical compounds and use of same in cancer and tauopathies |
WO2015130922A2 (en) | 2014-02-26 | 2015-09-03 | The Trustees Of The University Of Pennsylvania | Small molecule hsp70 inhibitors |
US10221171B2 (en) | 2015-01-09 | 2019-03-05 | The Regents Of The University Of California | Oxathiazole thiazolium Hsp 70 inhibitors |
US10208098B2 (en) | 2016-09-15 | 2019-02-19 | Council Of Scientific & Industrial Research | Recombinant protein-based method for the delivery of silencer RNA to target the brain |
CN112543595B (zh) | 2018-05-30 | 2022-11-01 | 莫尔豪斯医学院 | 抗微生物组合物,其制备方法和用途 |
-
2016
- 2016-12-19 WO PCT/US2016/067616 patent/WO2018118015A1/en active Application Filing
- 2016-12-19 US US15/383,454 patent/US10040831B2/en active Active
- 2016-12-19 CN CN201680092090.9A patent/CN110312549B/zh active Active
- 2016-12-19 EP EP16924332.6A patent/EP3554638B1/en active Active
-
2018
- 2018-07-09 US US16/030,430 patent/US10544193B2/en active Active
- 2018-12-19 CN CN201880097355.3A patent/CN112823025B/zh active Active
- 2018-12-19 WO PCT/US2018/066567 patent/WO2020013879A1/en unknown
- 2018-12-19 EP EP18926328.8A patent/EP3820489A4/en active Pending
Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20120121507A1 (en) * | 2009-04-17 | 2012-05-17 | Rana Filfil | Peptide ligands for clusterin and uses thereof |
CN103096932A (zh) * | 2010-06-14 | 2013-05-08 | 弗·哈夫曼-拉罗切有限公司 | 细胞穿透肽及其用途 |
WO2013052058A1 (en) * | 2011-10-07 | 2013-04-11 | Morehouse School Of Medicine | Antimicrobial compositions and methods of use thereof |
US20130089525A1 (en) * | 2011-10-07 | 2013-04-11 | Morehouse School Of Medicine | Antimicrobial compositions and methods of use thereof |
US20170369533A1 (en) * | 2011-12-15 | 2017-12-28 | Morehouse School Of Medicine | Compositions and methods for exosome targeted expression |
US20180140661A1 (en) * | 2016-11-18 | 2018-05-24 | City Of Hope | Peptide inhibitors of twist |
US20180170969A1 (en) * | 2016-12-19 | 2018-06-21 | Morehouse School Of Medicine | Compositions and methods for treating diseases by inhibiting exosome release |
Non-Patent Citations (1)
Title |
---|
MING-BO HUANG等: ""Role of Nef secretion modification region (SMR) peptides and the chaperone mortalin in breast cancer and leukemia cells",Ming-Bo Huang等, 《CANCER RESEARCH》,第78卷,第13期,第1869页", 《CANCER RESEARCH》, vol. 78, no. 13, pages 1869 * |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN113995848A (zh) * | 2021-09-29 | 2022-02-01 | 吉林大学 | 一种金纳米棒复合材料及其制备方法与应用 |
CN116970574A (zh) * | 2023-06-26 | 2023-10-31 | 广东省农业科学院动物卫生研究所 | 一种鹅源波形蛋白的用途、促进增殖鹅星状病毒的方法及用途、疫苗 |
CN116970574B (zh) * | 2023-06-26 | 2024-02-09 | 广东省农业科学院动物卫生研究所 | 一种鹅源波形蛋白的用途、促进增殖鹅星状病毒的方法及用途、疫苗 |
Also Published As
Publication number | Publication date |
---|---|
WO2018118015A1 (en) | 2018-06-28 |
EP3554638A4 (en) | 2020-08-19 |
EP3554638A1 (en) | 2019-10-23 |
US10040831B2 (en) | 2018-08-07 |
US10544193B2 (en) | 2020-01-28 |
CN112823025B (zh) | 2023-12-08 |
US20180170969A1 (en) | 2018-06-21 |
EP3554638B1 (en) | 2022-02-02 |
EP3820489A1 (en) | 2021-05-19 |
US20180305412A1 (en) | 2018-10-25 |
CN110312549B (zh) | 2021-06-29 |
CN110312549A (zh) | 2019-10-08 |
EP3820489A4 (en) | 2022-04-27 |
WO2020013879A1 (en) | 2020-01-16 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN112823025B (zh) | 用于通过抑制胞外体释放以治疗疾病的组成物及方法 | |
US11472846B2 (en) | Compositions and methods for treating diseases by inhibiting exosome release | |
US20230127248A1 (en) | Peptidomimetic macrocycles and formulations thereof | |
JP2020164547A (ja) | 癌の治療法 | |
WO2019161192A1 (en) | Engineered nanovesicles as checkpoint blockade for cancer immunotherapy | |
US20200093932A1 (en) | Treatment of cancer | |
TW200902043A (en) | Novel formulations for delivery of antiviral peptide therapeutics | |
US20220339259A1 (en) | Orally delivered therapeutical composition and use thereof | |
CN103442563A (zh) | 癌症治疗 | |
JP2010540528A (ja) | 治療的抗ウイルス性ペプチドの新規合成方法 | |
Wang et al. | CPP-mediated protein delivery in a noncovalent form: proof-of-concept for percutaneous and intranasal delivery | |
US20150111814A1 (en) | Novel compositions for promoting hiv-1 virolysis and methods using same | |
US20200392289A1 (en) | Biodegradable Polymer and Use Thereof | |
JP5898071B2 (ja) | 腫瘍成長の阻害剤としてのデルマセプチンb2 | |
US10251931B2 (en) | Cyclic peptides and methods using same | |
JP6857875B2 (ja) | 新規な細胞膜透過性ペプチド | |
US20230355708A1 (en) | Compositions for inhibiting viral entry and methods using same | |
US20220348617A1 (en) | Engineering broadly reactive human notch ligands as novel tools for biomedical applications | |
WO2020227682A1 (en) | Treating cancer | |
WO2022029810A1 (en) | Peptides able to bind angiotensin-converting enzyme 2 (ace2) and medical uses thereof |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant |