JP2018510917A - 抗癌治療剤 - Google Patents
抗癌治療剤 Download PDFInfo
- Publication number
- JP2018510917A JP2018510917A JP2018504078A JP2018504078A JP2018510917A JP 2018510917 A JP2018510917 A JP 2018510917A JP 2018504078 A JP2018504078 A JP 2018504078A JP 2018504078 A JP2018504078 A JP 2018504078A JP 2018510917 A JP2018510917 A JP 2018510917A
- Authority
- JP
- Japan
- Prior art keywords
- cancer
- capcna
- aoh39
- compounds
- compound
- 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
- 239000002246 antineoplastic agent Substances 0.000 title claims description 6
- 229940124597 therapeutic agent Drugs 0.000 title abstract description 6
- 230000003211 malignant effect Effects 0.000 claims abstract description 28
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 27
- 201000011510 cancer Diseases 0.000 claims abstract description 27
- 108050006400 Cyclin Proteins 0.000 claims abstract description 25
- 102000009339 Proliferating Cell Nuclear Antigen Human genes 0.000 claims abstract description 24
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 14
- 102000001708 Protein Isoforms Human genes 0.000 claims abstract description 12
- 108010029485 Protein Isoforms Proteins 0.000 claims abstract description 12
- 150000001875 compounds Chemical class 0.000 claims description 95
- 239000000203 mixture Substances 0.000 claims description 47
- 238000000034 method Methods 0.000 claims description 35
- 150000003839 salts Chemical class 0.000 claims description 15
- 206010006187 Breast cancer Diseases 0.000 claims description 10
- 208000026310 Breast neoplasm Diseases 0.000 claims description 10
- 206010029260 Neuroblastoma Diseases 0.000 claims description 10
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 9
- 230000004663 cell proliferation Effects 0.000 claims description 7
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 6
- 239000000969 carrier Substances 0.000 claims description 6
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 6
- 201000002528 pancreatic cancer Diseases 0.000 claims description 6
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 6
- 239000003085 diluting agent Substances 0.000 claims description 5
- 229940127089 cytotoxic agent Drugs 0.000 claims description 4
- 230000000973 chemotherapeutic effect Effects 0.000 claims description 2
- 230000002708 enhancing effect Effects 0.000 claims description 2
- 239000003814 drug Substances 0.000 abstract description 19
- 231100000135 cytotoxicity Toxicity 0.000 abstract description 8
- 230000003013 cytotoxicity Effects 0.000 abstract description 8
- 239000000126 substance Substances 0.000 abstract description 4
- 230000001093 anti-cancer Effects 0.000 abstract 1
- 210000004027 cell Anatomy 0.000 description 57
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 36
- 230000000694 effects Effects 0.000 description 21
- -1 cycloheteroalkyl Chemical group 0.000 description 19
- 125000000217 alkyl group Chemical group 0.000 description 15
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 15
- 229940002612 prodrug Drugs 0.000 description 14
- 239000000651 prodrug Substances 0.000 description 14
- 230000004543 DNA replication Effects 0.000 description 13
- 230000027455 binding Effects 0.000 description 12
- 150000003384 small molecules Chemical class 0.000 description 12
- 125000003118 aryl group Chemical group 0.000 description 11
- 229940079593 drug Drugs 0.000 description 11
- 239000002904 solvent Substances 0.000 description 11
- 238000006243 chemical reaction Methods 0.000 description 10
- 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 10
- 201000010099 disease Diseases 0.000 description 10
- 239000002953 phosphate buffered saline Substances 0.000 description 10
- 238000003556 assay Methods 0.000 description 9
- 230000003833 cell viability Effects 0.000 description 9
- 125000001072 heteroaryl group Chemical group 0.000 description 9
- 230000005764 inhibitory process Effects 0.000 description 9
- 230000003993 interaction Effects 0.000 description 9
- 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 8
- 125000000753 cycloalkyl group Chemical group 0.000 description 8
- 238000000338 in vitro Methods 0.000 description 8
- 230000000875 corresponding effect Effects 0.000 description 7
- 125000000392 cycloalkenyl group Chemical group 0.000 description 7
- 125000000524 functional group Chemical group 0.000 description 7
- 230000012010 growth Effects 0.000 description 7
- 125000004404 heteroalkyl group Chemical group 0.000 description 7
- 125000005842 heteroatom Chemical group 0.000 description 7
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 7
- 210000001519 tissue Anatomy 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- 230000033616 DNA repair Effects 0.000 description 6
- 125000003710 aryl alkyl group Chemical group 0.000 description 6
- 238000009472 formulation Methods 0.000 description 6
- 125000004446 heteroarylalkyl group Chemical group 0.000 description 6
- 230000001404 mediated effect Effects 0.000 description 6
- 108090000623 proteins and genes Proteins 0.000 description 6
- 102000004169 proteins and genes Human genes 0.000 description 6
- 230000035899 viability Effects 0.000 description 6
- 108020004414 DNA Proteins 0.000 description 5
- 230000009471 action Effects 0.000 description 5
- 125000003342 alkenyl group Chemical group 0.000 description 5
- 125000000304 alkynyl group Chemical group 0.000 description 5
- 210000000481 breast Anatomy 0.000 description 5
- 208000035475 disorder Diseases 0.000 description 5
- 239000002552 dosage form Substances 0.000 description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 5
- 238000007911 parenteral administration Methods 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 239000012453 solvate Substances 0.000 description 5
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 5
- 230000001225 therapeutic effect Effects 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 238000012054 celltiter-glo Methods 0.000 description 4
- 238000002648 combination therapy Methods 0.000 description 4
- 230000002950 deficient Effects 0.000 description 4
- 230000001419 dependent effect Effects 0.000 description 4
- 229960004679 doxorubicin Drugs 0.000 description 4
- 125000001188 haloalkyl group Chemical group 0.000 description 4
- 230000036541 health Effects 0.000 description 4
- 150000004677 hydrates Chemical class 0.000 description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 4
- 238000001727 in vivo Methods 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 108090000765 processed proteins & peptides Proteins 0.000 description 4
- 238000006467 substitution reaction Methods 0.000 description 4
- 231100000419 toxicity Toxicity 0.000 description 4
- 230000001988 toxicity Effects 0.000 description 4
- 108700020463 BRCA1 Proteins 0.000 description 3
- 102000036365 BRCA1 Human genes 0.000 description 3
- 101150072950 BRCA1 gene Proteins 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- 108090000652 Flap endonucleases Proteins 0.000 description 3
- 102000004150 Flap endonucleases Human genes 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- XDMCWZFLLGVIID-SXPRBRBTSA-N O-(3-O-D-galactosyl-N-acetyl-beta-D-galactosaminyl)-L-serine Chemical compound CC(=O)N[C@H]1[C@H](OC[C@H]([NH3+])C([O-])=O)O[C@H](CO)[C@H](O)[C@@H]1OC1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 XDMCWZFLLGVIID-SXPRBRBTSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 125000002252 acyl group Chemical group 0.000 description 3
- 125000004442 acylamino group Chemical group 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 125000003277 amino group Chemical group 0.000 description 3
- 125000004122 cyclic group Chemical group 0.000 description 3
- 201000007281 estrogen-receptor positive breast cancer Diseases 0.000 description 3
- 125000005843 halogen group Chemical group 0.000 description 3
- 238000001802 infusion Methods 0.000 description 3
- 238000007918 intramuscular administration Methods 0.000 description 3
- 238000001990 intravenous administration Methods 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 210000001616 monocyte Anatomy 0.000 description 3
- 210000005259 peripheral blood Anatomy 0.000 description 3
- 239000011886 peripheral blood Substances 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 125000006239 protecting group Chemical group 0.000 description 3
- 230000004850 protein–protein interaction Effects 0.000 description 3
- 230000008439 repair process Effects 0.000 description 3
- 230000004044 response Effects 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 238000007920 subcutaneous administration Methods 0.000 description 3
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 2
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 2
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 230000005778 DNA damage Effects 0.000 description 2
- 231100000277 DNA damage Toxicity 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 2
- 102000018779 Replication Protein C Human genes 0.000 description 2
- 108010027647 Replication Protein C Proteins 0.000 description 2
- BUGBHKTXTAQXES-UHFFFAOYSA-N Selenium Chemical compound [Se] BUGBHKTXTAQXES-UHFFFAOYSA-N 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 125000003282 alkyl amino group Chemical group 0.000 description 2
- 125000004103 aminoalkyl group Chemical group 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 230000005907 cancer growth Effects 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 230000003915 cell function Effects 0.000 description 2
- 230000010261 cell growth Effects 0.000 description 2
- 238000011260 co-administration Methods 0.000 description 2
- 125000004663 dialkyl amino group Chemical group 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 230000008030 elimination Effects 0.000 description 2
- 238000003379 elimination reaction Methods 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 230000001747 exhibiting effect Effects 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 125000000623 heterocyclic group Chemical group 0.000 description 2
- 239000007943 implant Substances 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 239000002502 liposome Substances 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 230000002503 metabolic effect Effects 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 238000003032 molecular docking Methods 0.000 description 2
- 230000000877 morphologic effect Effects 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- IQZPDFORWZTSKT-UHFFFAOYSA-N nitrosulphonic acid Chemical compound OS(=O)(=O)[N+]([O-])=O IQZPDFORWZTSKT-UHFFFAOYSA-N 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 210000003819 peripheral blood mononuclear cell Anatomy 0.000 description 2
- 230000003285 pharmacodynamic effect Effects 0.000 description 2
- 229910052698 phosphorus Inorganic materials 0.000 description 2
- 239000011574 phosphorus Substances 0.000 description 2
- 125000003367 polycyclic group Chemical group 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 102000004196 processed proteins & peptides Human genes 0.000 description 2
- 230000002062 proliferating effect Effects 0.000 description 2
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 230000010076 replication Effects 0.000 description 2
- 229910052711 selenium Inorganic materials 0.000 description 2
- 239000011669 selenium Substances 0.000 description 2
- 230000009870 specific binding Effects 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 125000003107 substituted aryl group Chemical group 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- 239000011593 sulfur Substances 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 125000003396 thiol group Chemical class [H]S* 0.000 description 2
- 230000003442 weekly effect Effects 0.000 description 2
- CRDNMYFJWFXOCH-YPKPFQOOSA-N (3z)-3-(3-oxo-1h-indol-2-ylidene)-1h-indol-2-one Chemical class N/1C2=CC=CC=C2C(=O)C\1=C1/C2=CC=CC=C2NC1=O CRDNMYFJWFXOCH-YPKPFQOOSA-N 0.000 description 1
- 108090000531 Amidohydrolases Proteins 0.000 description 1
- 102000004092 Amidohydrolases Human genes 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 1
- 238000003734 CellTiter-Glo Luminescent Cell Viability Assay Methods 0.000 description 1
- 102000012410 DNA Ligases Human genes 0.000 description 1
- 108010061982 DNA Ligases Proteins 0.000 description 1
- 102000007528 DNA Polymerase III Human genes 0.000 description 1
- 108010071146 DNA Polymerase III Proteins 0.000 description 1
- 102100034157 DNA mismatch repair protein Msh2 Human genes 0.000 description 1
- 230000006820 DNA synthesis Effects 0.000 description 1
- 102000016928 DNA-directed DNA polymerase Human genes 0.000 description 1
- 108010014303 DNA-directed DNA polymerase Proteins 0.000 description 1
- 108010042407 Endonucleases Proteins 0.000 description 1
- 102000004533 Endonucleases Human genes 0.000 description 1
- 108090000371 Esterases Proteins 0.000 description 1
- 108091006027 G proteins Proteins 0.000 description 1
- 102000030782 GTP binding Human genes 0.000 description 1
- 108091000058 GTP-Binding Proteins 0.000 description 1
- 101001134036 Homo sapiens DNA mismatch repair protein Msh2 Proteins 0.000 description 1
- 206010022086 Injection site pain Diseases 0.000 description 1
- 102000015617 Janus Kinases Human genes 0.000 description 1
- 108010024121 Janus Kinases Proteins 0.000 description 1
- 229910015837 MSH2 Inorganic materials 0.000 description 1
- 231100000002 MTT assay Toxicity 0.000 description 1
- 238000000134 MTT assay Methods 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 206010027452 Metastases to bone Diseases 0.000 description 1
- QPJVMBTYPHYUOC-UHFFFAOYSA-N Methyl benzoate Natural products COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 description 1
- 102000016397 Methyltransferase Human genes 0.000 description 1
- 108060004795 Methyltransferase Proteins 0.000 description 1
- 101150008755 PCNA gene Proteins 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 101150099493 STAT3 gene Proteins 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 241000534944 Thia Species 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- 201000006083 Xeroderma Pigmentosum Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 125000002015 acyclic group Chemical group 0.000 description 1
- 125000004423 acyloxy group Chemical group 0.000 description 1
- 125000005041 acyloxyalkyl group Chemical group 0.000 description 1
- 125000005035 acylthio group Chemical group 0.000 description 1
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 1
- 102000035181 adaptor proteins Human genes 0.000 description 1
- 108091005764 adaptor proteins Proteins 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 125000006323 alkenyl amino group Chemical group 0.000 description 1
- 125000005090 alkenylcarbonyl group Chemical group 0.000 description 1
- 125000003302 alkenyloxy group Chemical group 0.000 description 1
- 125000005108 alkenylthio group Chemical group 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 1
- 125000005205 alkoxycarbonyloxyalkyl group Chemical group 0.000 description 1
- 125000004448 alkyl carbonyl group Chemical group 0.000 description 1
- 125000004644 alkyl sulfinyl group Chemical group 0.000 description 1
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 1
- 125000004414 alkyl thio group Chemical group 0.000 description 1
- 125000006319 alkynyl amino group Chemical group 0.000 description 1
- 125000005087 alkynylcarbonyl group Chemical group 0.000 description 1
- 125000005133 alkynyloxy group Chemical group 0.000 description 1
- 125000005109 alkynylthio group Chemical group 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 239000013011 aqueous formulation Substances 0.000 description 1
- 125000001691 aryl alkyl amino group Chemical group 0.000 description 1
- 125000005099 aryl alkyl carbonyl group Chemical group 0.000 description 1
- 125000004659 aryl alkyl thio group Chemical group 0.000 description 1
- 125000002102 aryl alkyloxo group Chemical group 0.000 description 1
- 125000001769 aryl amino group Chemical group 0.000 description 1
- 125000005129 aryl carbonyl group Chemical group 0.000 description 1
- 125000005135 aryl sulfinyl group Chemical group 0.000 description 1
- 125000004391 aryl sulfonyl group Chemical group 0.000 description 1
- 125000005110 aryl thio group Chemical group 0.000 description 1
- 125000004104 aryloxy group Chemical group 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 125000004604 benzisothiazolyl group Chemical group S1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000004603 benzisoxazolyl group Chemical group O1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 239000003124 biologic agent Substances 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 210000000069 breast epithelial cell Anatomy 0.000 description 1
- 150000004657 carbamic acid derivatives Chemical class 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 1
- 125000002837 carbocyclic group Chemical group 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 150000007942 carboxylates Chemical class 0.000 description 1
- 150000001733 carboxylic acid esters Chemical class 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000012820 cell cycle checkpoint Effects 0.000 description 1
- 238000003570 cell viability assay Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000002759 chromosomal effect Effects 0.000 description 1
- 229940121657 clinical drug Drugs 0.000 description 1
- 230000002301 combined effect Effects 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 125000004465 cycloalkenyloxy group Chemical group 0.000 description 1
- 125000000000 cycloalkoxy group Chemical group 0.000 description 1
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 description 1
- 125000006310 cycloalkyl amino group Chemical group 0.000 description 1
- 125000006254 cycloalkyl carbonyl group Chemical group 0.000 description 1
- 125000005356 cycloalkylalkenyl group Chemical group 0.000 description 1
- 125000005366 cycloalkylthio group Chemical group 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 230000007123 defense Effects 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 235000006694 eating habits Nutrition 0.000 description 1
- 238000001962 electrophoresis Methods 0.000 description 1
- 210000002615 epidermis Anatomy 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 201000007280 estrogen-receptor negative breast cancer Diseases 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 230000009036 growth inhibition Effects 0.000 description 1
- 125000001475 halogen functional group Chemical group 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000005114 heteroarylalkoxy group Chemical group 0.000 description 1
- 125000005367 heteroarylalkylthio group Chemical group 0.000 description 1
- 125000005241 heteroarylamino group Chemical group 0.000 description 1
- 125000005223 heteroarylcarbonyl group Chemical group 0.000 description 1
- 125000005553 heteroaryloxy group Chemical group 0.000 description 1
- 125000005150 heteroarylsulfinyl group Chemical group 0.000 description 1
- 125000005143 heteroarylsulfonyl group Chemical group 0.000 description 1
- 125000005368 heteroarylthio group Chemical group 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000007915 intraurethral administration Methods 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 238000002483 medication Methods 0.000 description 1
- 239000012907 medicinal substance Substances 0.000 description 1
- 125000001570 methylene group Chemical class [H]C([H])([*:1])[*:2] 0.000 description 1
- 239000003094 microcapsule Substances 0.000 description 1
- 239000004005 microsphere Substances 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000002105 nanoparticle Substances 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 210000003757 neuroblast Anatomy 0.000 description 1
- 230000020520 nucleotide-excision repair Effects 0.000 description 1
- GYCKQBWUSACYIF-UHFFFAOYSA-N o-hydroxybenzoic acid ethyl ester Natural products CCOC(=O)C1=CC=CC=C1O GYCKQBWUSACYIF-UHFFFAOYSA-N 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 229940126701 oral medication Drugs 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 239000003002 pH adjusting agent Substances 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 230000002974 pharmacogenomic effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 229920002401 polyacrylamide Polymers 0.000 description 1
- 239000008389 polyethoxylated castor oil Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000006916 protein interaction Effects 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 230000001698 pyrogenic effect Effects 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 238000006862 quantum yield reaction Methods 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 125000004621 quinuclidinyl group Chemical group N12C(CC(CC1)CC2)* 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000006798 recombination Effects 0.000 description 1
- 238000005215 recombination Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 238000004088 simulation Methods 0.000 description 1
- 238000009097 single-agent therapy Methods 0.000 description 1
- 239000008137 solubility enhancer Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 102000009076 src-Family Kinases Human genes 0.000 description 1
- 108010087686 src-Family Kinases Proteins 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000012058 sterile packaged powder Substances 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000005247 tetrazinyl group Chemical group N1=NN=NC(=C1)* 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 150000007970 thio esters Chemical class 0.000 description 1
- 150000003558 thiocarbamic acid derivatives Chemical class 0.000 description 1
- 238000013519 translation Methods 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 231100000747 viability assay Toxicity 0.000 description 1
- 238000003026 viability measurement method Methods 0.000 description 1
Classifications
-
- 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
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
- A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Organic Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Pain & Pain Management (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Description
本発明は、一部、国防総省の議会指定医学研究プログラム(CDMRP)である、乳癌研究プログラムにより授与された、助成金番号W81XWH−07−1−0707;国立衛生研究所/国立癌研究所により授与された、助成金番号RO1CA121289;およびA.N.N.A.基金からの恵与のもと、政府支援により行った。
本明細書に記載の発明は、同等の非悪性細胞に対する細胞毒性と比較して、増殖細胞核抗原の癌特異的アイソフォーム(caPCNA)を発現する悪性細胞に対して優先的な細胞毒性を示す抗癌治療剤、該薬剤を含む医薬組成物およびそれらの癌治療における使用に関する。
増殖細胞核抗原(PCNA)は、DNA複製、DNA修復、染色体組換え、細胞周期チェックポイント制御および他の細胞増殖活動の過程において重要な役割を果たす。アダプタータンパク質である複製因子C(RFC)と共に、PCNAは、DNAポリメラーゼδおよびεに対するドッキング点である移動クランプを形成する。酸性および塩基性の両方の等電点(pI)を示す増殖細胞核抗原(PCNA)の種々のアイソフォームが示されている。悪性および非悪性の双方の乳房細胞および組織からの二次元ポリアクリルアミド電気泳動によるPCNA(非悪性の場合は、非悪性PCNAまたはnmPCNAと称される)の分析は、悪性細胞においてのみ、酸性形態のPCNA(癌特異的PCNAまたはPCNAまたはcsPCNAまたはcaPCNA、本明細書でcaPCNAと称される)が存在することを明らかにした。これら2つの形態のPCNA間の等電点におけるこの差異は、翻訳後にPCNAポリペプチドを修飾する悪性細胞の能力における変化に起因し、PCNA遺伝子内での遺伝子変化によるものではないように見える。
本発明によると、小分子治療剤は、caPCNAが関与するタンパク質−タンパク質相互作用を阻害する特異的結合様式を介してそれらの作用を発揮する。caPCNAと結合すると、これらの分子はcaPCNAを減少させるか、またはcaPCNAがその本来の結合パートナーのセットと相互作用するのを妨げる。この結合パートナー相互作用の破壊は、caPCNAおよびその結合パートナーの双方を必要とする特異的細胞機能(例えば、DNA複製およびDNA修復)の阻害をもたらす。
細胞生存率に対するAOH39の効果は、記載した濃度のAOH39または薬物非含有リン酸緩衝生理食塩水(PBS)/DMSO対照と72時間インキュベートした乳癌および神経芽腫細胞株の生存率を試験することにより、調査された。図2を参照;HCC1937はBRCA1欠損乳癌細胞株であり;MCF7はER+乳癌細胞株であり;MCF10Aは、非悪性であるが、不死化乳房細胞株であり;SK−N−AS、SK−N−BE2cおよびSK−N−DZ株は、神経芽腫細胞株であり;X軸には調査された種々の細胞が列挙されている。Y軸は細胞増殖を、AOH39を添加していないPBS/DMSO存在下で生育させた培養物中の増殖率として示す。増殖はCellTiter Glo Assay(Promega社、Madison,WI)(https://www.promega.com/products/cell−health−and−metabolism/cell−viability−assays/celltiter−glo−luminescent−cell−viability−assay/)を使用して観察した。ヒストグラムはプリズム6を用いて作成した。
インビトロDNA複製活性は、標準的なT−抗原およびSV40組織依存インビトロDNA複製反応(L. Malkas et al., Biochemistry 29: 6362-6374 (1990))を用いて決定され、阻害率はAOH39の代わりにTris−HCl/DMSOを含む反応と比較して決定された。反応は、反応混合物へのT−抗原の添加で開始された。5μMの濃度でおよそ50%、および10μMで75%以上まで複製を阻害するAOH39と共に、結果を図3に示す。
AOH39のSV40組織依存インビトロDNA複製過程を阻害する能力とMCF7細胞生存率の間には厳密な相関が存在する、図4。細胞生存率は、10μMのAOH39で72時間インキュベート後、MTTアッセイを使用して比色分析で決定された。インビトロDNA複製活性は、標準的なT−抗原およびSV40起源依存インビトロDNA複製(L. Malkas et al., Biochemistry, 29, 6362-6374 (1990))を使用して決定され、阻害率は、活性アッセイについてはAOH39の代わりにTris−HCl/DMSOを、生存率アッセイについてはPBS/DMSOを含む反応と比較して決定された。AOH39は、化合物の代わりにPBS/DMSOを含む対照複製反応と比較して、有意にDNA複製を阻害し、阻害はMCF7細胞生存率における有意な減少と厳密に相関した。
図5は、caPCNAのPIP Box相互作用ドメインとのAOH39の相互作用のエネルギー最小化の結果を示す。AOH39の結合様式は、初めはオールアラウンドドッキング(AAD)(Nam S, Wen W, Schroeder A, Herrmann A, Yu H, Cheng X, Merz KH, Eisenbrand G, Li H, Yuan YC, Jove R, “Dual inhibition of Janus and Src family kinases by novel indirubin derivative blocks constitutively-activated Stat3 signaling associated with apoptosis of human pancreatic cancer cells”, Mol. Oncol. 2013 Jun;7(3):369-78. doi: 10.1016/j.molonc.2012.10.013 PMID: 23206899)を使用して構築され、メタダイナミクス(Laio, A.; Parrinello, M. (2002). "Escaping free-energy minima". Proceedings of the National Academy of Sciences of the United States of America 99 (20): 12562-12566.)により50ナノ秒シミュレーションで改良された。caPCNAに対するAOH39の結合アフィニティは、Schrodinger Glide DockingソフトウェアをXP精度で用いて、−4.62kcal/molであると予測される。
癌および非癌細胞株の増殖に対するAOH39の効果を調査し、結果を図6に要約した。AOH39または薬物欠乏DMSO対照とインキュベートした乳癌および神経芽腫細胞株の生存率。増殖はCellTiter Glo Assay(Promega社、Madison,WI)(https://www.promega.com/products/cell−health−and−metabolism/cell−viability−assays/celltiter−glo−luminescent−cell−viability−assay/)を使用して観察した。X軸はμMにおけるAOH39濃度のlog値であり、0は1μMに対応し、1は10μMに対応する。グラフは、プリズム6を用いて生成させた。MDA−MB231およびMDA−MB468はER−乳癌細胞株であり;SK−N−AS株、SK−N−BE2c株、SK−N−DZ株は神経芽腫細胞株であり;LAN5細胞は神経芽腫骨転移であり;HCC1937はBRCA1欠損乳癌細胞株であり;MCF7はER+乳癌細胞株であり;MCF10Aは、非悪性であるが、不死化乳房細胞株であり;PBMCは末梢血単球(増殖している正常細胞)である。X軸はAOH39濃度の対数としてプロットされ、1.0が10μMに対応する。Y軸は細胞増殖を、AOH39を添加していないPBS/DMSO中の増殖率として示す。
膵臓癌細胞株の増殖に対するAOH39の効果を図7に要約する。PBS/DMSO(薬物無し)と比較して示された濃度で、AOH39とインキュベートしたPanc1およびPanc2細胞株の生存率をY軸上にプロットし、そしてX軸はμMにおけるAOH39濃度を示す。増殖はCellTiter Glo Assay(Promega社、Madison,WI)(https://www.promega.com/products/cell−health−and−metabolism/cell−viability−assays/celltiter−glo−luminescent−cell−viability−assay/)を使用して観察した。グラフは、プリズム6を用いて生成させた。
種々の悪性および非悪性細胞株における細胞生存率へのAOH39の効果を表1ならびに図8および図9に示す。
Claims (8)
- 治療有効量の式
- 増殖細胞核抗原の癌特異的(関連性)アイソフォーム(caPCNA)を発現する悪性細胞の細胞増殖を減少させるための、請求項1に記載の化合物もしくはその置換誘導体、またはその薬学的に許容される塩の使用方法。
- 請求項1に記載の化合物もしくはその置換誘導体、またはその薬学的に許容される塩を含み、さらに1以上の担体、希釈剤もしくは賦形剤またはそれらの組合せを含む医薬組成物。
- 癌が乳癌である、請求項1〜3のいずれか一項に記載の方法、使用または組成物。
- 癌が膵臓癌である、請求項1〜3のいずれか一項に記載の方法、使用または組成物。
- 癌が神経芽腫である、請求項1〜3のいずれか一項に記載の方法、使用または組成物。
- 該使用が別の化学療法的方法を増強するためである、請求項1〜6のいずれか一項に記載の方法または使用。
- 請求項3に記載の化合物およびさらなる化学治療剤を含む医薬組成物。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US14/684,259 US10420840B2 (en) | 2015-04-10 | 2015-04-10 | Anticancer therapeutic agents |
US14/684,259 | 2015-04-10 | ||
PCT/US2016/026619 WO2016164707A1 (en) | 2015-04-10 | 2016-04-08 | Anticancer therapeutic agents |
Publications (3)
Publication Number | Publication Date |
---|---|
JP2018510917A true JP2018510917A (ja) | 2018-04-19 |
JP2018510917A5 JP2018510917A5 (ja) | 2019-05-09 |
JP6748704B2 JP6748704B2 (ja) | 2020-09-02 |
Family
ID=57072079
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2018504078A Active JP6748704B2 (ja) | 2015-04-10 | 2016-04-08 | 抗癌治療剤 |
Country Status (9)
Country | Link |
---|---|
US (1) | US10420840B2 (ja) |
EP (2) | EP3280261B1 (ja) |
JP (1) | JP6748704B2 (ja) |
CN (1) | CN107404876B (ja) |
AU (1) | AU2016245886B2 (ja) |
BR (1) | BR122023024844A2 (ja) |
CA (1) | CA2978965C (ja) |
PL (1) | PL3280261T3 (ja) |
WO (1) | WO2016164707A1 (ja) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2023172880A2 (en) * | 2022-03-07 | 2023-09-14 | City Of Hope | Pcna inhibitors and uses thereof |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2009527498A (ja) * | 2006-02-17 | 2009-07-30 | インディアナ ユニバーシティー リサーチ アンド テクノロジー コーポレーション | 癌におけるcaPCNA相互作用のペプチドによる抑制 |
JP2011529079A (ja) * | 2008-07-24 | 2011-12-01 | インディアナ ユニバーシティー リサーチ アンド テクノロジー コーポレーション | 癌のペプチド治療剤 |
JP2014511839A (ja) * | 2011-03-23 | 2014-05-19 | インディアナ・ユニバーシティ・リサーチ・アンド・テクノロジー・コーポレイション | 抗癌治療薬 |
Family Cites Families (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5627165A (en) | 1990-06-13 | 1997-05-06 | Drug Innovation & Design, Inc. | Phosphorous prodrugs and therapeutic delivery systems using same |
US20050037090A1 (en) | 1998-12-23 | 2005-02-17 | Mckearn John P. | Combination therapy including a cyclooxygenase-2 inhibitor and an antineoplastic agent |
JP2008539271A (ja) | 2005-04-27 | 2008-11-13 | インディアナ ユニバーシティー リサーチ アンド テクノロジー コーポレーション | csPCNAイソ型抗体およびその使用 |
BRPI0611703A2 (pt) * | 2005-06-27 | 2011-12-20 | Univ Indiana Res & Tech Corp | modificações da isoforma do cspcna e seus usos |
US20090123487A1 (en) | 2007-09-19 | 2009-05-14 | Katia Rothhaar | Precursors and enzymes associated with post translational modification of proteins implicated in isoform generation of PCNA |
WO2009079451A2 (en) | 2007-12-14 | 2009-06-25 | The Cleveland Clinic Foundation | Compositions and methods of promoting wound healing |
GB0808282D0 (en) | 2008-05-07 | 2008-06-11 | Medical Res Council | Compounds for use in stabilizing p53 mutants |
US20120195978A1 (en) * | 2009-10-07 | 2012-08-02 | Indiana University Research And Technology Corpora | Capcna peptide therapeutics for cancer |
JP6966996B2 (ja) * | 2015-09-17 | 2021-11-17 | シティ・オブ・ホープCity of Hope | Pcna阻害剤 |
-
2015
- 2015-04-10 US US14/684,259 patent/US10420840B2/en active Active
-
2016
- 2016-04-08 CN CN201680018509.6A patent/CN107404876B/zh active Active
- 2016-04-08 JP JP2018504078A patent/JP6748704B2/ja active Active
- 2016-04-08 WO PCT/US2016/026619 patent/WO2016164707A1/en active Application Filing
- 2016-04-08 BR BR122023024844-9A patent/BR122023024844A2/pt not_active Application Discontinuation
- 2016-04-08 PL PL16777344T patent/PL3280261T3/pl unknown
- 2016-04-08 EP EP16777344.9A patent/EP3280261B1/en active Active
- 2016-04-08 AU AU2016245886A patent/AU2016245886B2/en active Active
- 2016-04-08 EP EP20216249.1A patent/EP3878444A1/en active Pending
- 2016-04-08 CA CA2978965A patent/CA2978965C/en active Active
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2009527498A (ja) * | 2006-02-17 | 2009-07-30 | インディアナ ユニバーシティー リサーチ アンド テクノロジー コーポレーション | 癌におけるcaPCNA相互作用のペプチドによる抑制 |
JP2011529079A (ja) * | 2008-07-24 | 2011-12-01 | インディアナ ユニバーシティー リサーチ アンド テクノロジー コーポレーション | 癌のペプチド治療剤 |
JP2014511839A (ja) * | 2011-03-23 | 2014-05-19 | インディアナ・ユニバーシティ・リサーチ・アンド・テクノロジー・コーポレイション | 抗癌治療薬 |
Non-Patent Citations (3)
Title |
---|
DILLEHAY, KELSEY L. ET AL., PHARMACOLOGY RESEARCH & PERSPECTIVES, vol. 3, no. 2, JPN6020006805, 2 February 2015 (2015-02-02), pages 1 - 14, ISSN: 0004219343 * |
PUNCHIHEWA, CHANDANAMALI ET AL., JOURNAL OF BIOLOGICAL CHEMISTRY, vol. 287, no. 17, JPN6020006806, 20 April 2012 (2012-04-20), pages 14289 - 14300, ISSN: 0004219344 * |
TAN, ZONGQING ET AL., MOLECULAR PHARMACOLOGY, vol. 81, no. 6, JPN6020006804, 2012, pages 811 - 819, ISSN: 0004219342 * |
Also Published As
Publication number | Publication date |
---|---|
EP3280261B1 (en) | 2020-12-23 |
EP3280261A1 (en) | 2018-02-14 |
US10420840B2 (en) | 2019-09-24 |
CA2978965A1 (en) | 2016-10-13 |
PL3280261T3 (pl) | 2021-09-06 |
JP6748704B2 (ja) | 2020-09-02 |
CA2978965C (en) | 2023-11-14 |
CN107404876B (zh) | 2023-04-14 |
BR122023024844A2 (pt) | 2024-01-23 |
EP3878444A1 (en) | 2021-09-15 |
EP3280261A4 (en) | 2018-12-12 |
BR112017019983A2 (pt) | 2018-06-19 |
AU2016245886A1 (en) | 2017-10-12 |
CN107404876A (zh) | 2017-11-28 |
US20160296482A1 (en) | 2016-10-13 |
WO2016164707A1 (en) | 2016-10-13 |
AU2016245886B2 (en) | 2020-04-30 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US20170259081A1 (en) | Methods for regulating cell mitosis by inhibiting serine/threonine phosphatase | |
RU2316326C2 (ru) | Способ и композиция для лечения ракового заболевания, тозилат и фармацевтически приемлемые соли n-(4-хлор-3-(трифторметил)фенил)-n'-(4-(2-(n-метилкарбамоил)-4-пиридилокси)фенил)мочевины | |
JP6158180B2 (ja) | 乳がんの処置 | |
US20100029683A1 (en) | Methods for regulating cell mitosis by inhibiting serine/threonine phosphateses | |
CN114569606B (zh) | 吲哚啉酮化合物的用途 | |
EP1968981A2 (en) | A method of treating tumors with azaxanthones | |
US20130345231A1 (en) | Anticancer therapeutic agents | |
BR112012019691B1 (pt) | Métodos in vitro para reduzir a atividade de uma proteína, ou para alterar a progressão do ciclo celular eucariótico, composto para a inibição de rpa, seus usos e uso de um composto a ou um sal farmaceuticamente aceitável do mesmo | |
US20230046317A1 (en) | Inhibitors of Glutathione S-Transferases (GSTS) and NAD(P)H:Quinone Oxidoreductase 1 (NQO1), Pharmaceutical Compositions, and Uses in Managing Cancer | |
JP6748704B2 (ja) | 抗癌治療剤 | |
KR20220008870A (ko) | 노치-활성화 유방암을 치료하기 위한 비스플루오로알킬-1,4-벤조디아제피논 화합물 | |
KR20140144215A (ko) | 오로라 키나제 저해제를 사용하는 암 치료 방법 | |
WO2013138600A1 (en) | Radioprotector compounds | |
BR112017019983B1 (pt) | Agentes terapêuticos anticâncer | |
CN112999236B (zh) | 乌本苷用于治疗脑干胶质瘤的用途 | |
WO2023175615A1 (en) | Arts mimetic componds and combinations thereof for treating high-risk neuroblastoma | |
WO2020205608A1 (en) | Uses of androgen receptor antagonists and jnk pathway inhibitors, and pharmaceutical compositions related thereto | |
CA3224123A1 (en) | Small molecule inhibition of deubiquitinating enzyme josephin domain containing 1 (josd1) as a targeted therapy for leukemias with mutant janus kinase 2 (jak2) | |
JP2023530734A (ja) | アイソフォーム特異的アルデヒドデヒドロゲナーゼ阻害剤 | |
JP2019532937A (ja) | Rnaポリメラーゼi阻害に基づく、がんの併用治療戦略 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20190322 |
|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20190322 |
|
A977 | Report on retrieval |
Free format text: JAPANESE INTERMEDIATE CODE: A971007 Effective date: 20200122 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20200225 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20200312 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20200721 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20200807 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 6748704 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |