EP3679053A1 - High affinity cxcr4 selective binding conjugate and method for using the same - Google Patents
High affinity cxcr4 selective binding conjugate and method for using the sameInfo
- Publication number
- EP3679053A1 EP3679053A1 EP18852912.7A EP18852912A EP3679053A1 EP 3679053 A1 EP3679053 A1 EP 3679053A1 EP 18852912 A EP18852912 A EP 18852912A EP 3679053 A1 EP3679053 A1 EP 3679053A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- ipr
- high affinity
- selective binding
- binding ligand
- peptide conjugate
- 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.)
- Pending
Links
- 230000027455 binding Effects 0.000 title claims abstract description 75
- 238000000034 method Methods 0.000 title claims description 40
- 101100441540 Xenopus laevis cxcr4-a gene Proteins 0.000 title 1
- 101100441541 Xenopus laevis cxcr4-b gene Proteins 0.000 title 1
- 101000922348 Homo sapiens C-X-C chemokine receptor type 4 Proteins 0.000 claims abstract description 108
- 102100031650 C-X-C chemokine receptor type 4 Human genes 0.000 claims abstract description 107
- 150000001875 compounds Chemical class 0.000 claims abstract description 75
- 239000000863 peptide conjugate Substances 0.000 claims abstract description 62
- 239000003446 ligand Substances 0.000 claims abstract description 59
- 239000000203 mixture Substances 0.000 claims abstract description 38
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 37
- 239000003814 drug Substances 0.000 claims abstract description 34
- 239000012216 imaging agent Substances 0.000 claims abstract description 31
- 150000003839 salts Chemical class 0.000 claims abstract description 25
- 238000003384 imaging method Methods 0.000 claims abstract description 24
- 229940124597 therapeutic agent Drugs 0.000 claims abstract description 24
- 239000000032 diagnostic agent Substances 0.000 claims abstract description 22
- 229940039227 diagnostic agent Drugs 0.000 claims abstract description 22
- 125000000524 functional group Chemical group 0.000 claims abstract description 18
- 208000031886 HIV Infections Diseases 0.000 claims abstract description 11
- 208000037357 HIV infectious disease Diseases 0.000 claims abstract description 11
- 208000033519 human immunodeficiency virus infectious disease Diseases 0.000 claims abstract description 11
- 125000001151 peptidyl group Chemical group 0.000 claims abstract description 11
- 125000000539 amino acid group Chemical group 0.000 claims abstract description 6
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 84
- -1 D- Dab Chemical compound 0.000 claims description 38
- 229960001592 paclitaxel Drugs 0.000 claims description 32
- 201000011510 cancer Diseases 0.000 claims description 28
- 229910052717 sulfur Inorganic materials 0.000 claims description 22
- 125000004434 sulfur atom Chemical group 0.000 claims description 22
- FFFHZYDWPBMWHY-VKHMYHEASA-N L-homocysteine Chemical class OC(=O)[C@@H](N)CCS FFFHZYDWPBMWHY-VKHMYHEASA-N 0.000 claims description 20
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 claims description 20
- 235000018417 cysteine Nutrition 0.000 claims description 19
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 claims description 18
- 239000003795 chemical substances by application Substances 0.000 claims description 15
- 229930012538 Paclitaxel Natural products 0.000 claims description 14
- 230000002285 radioactive effect Effects 0.000 claims description 14
- 239000008194 pharmaceutical composition Substances 0.000 claims description 13
- AHLPHDHHMVZTML-SCSAIBSYSA-N D-Ornithine Chemical compound NCCC[C@@H](N)C(O)=O AHLPHDHHMVZTML-SCSAIBSYSA-N 0.000 claims description 12
- 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 12
- PECYZEOJVXMISF-UWTATZPHSA-N 3-amino-D-alanine Chemical compound NC[C@@H](N)C(O)=O PECYZEOJVXMISF-UWTATZPHSA-N 0.000 claims description 10
- KDXKERNSBIXSRK-RXMQYKEDSA-N D-lysine Chemical compound NCCCC[C@@H](N)C(O)=O KDXKERNSBIXSRK-RXMQYKEDSA-N 0.000 claims description 10
- 210000004027 cell Anatomy 0.000 claims description 10
- 239000003937 drug carrier Substances 0.000 claims description 10
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 10
- DKIDEFUBRARXTE-UHFFFAOYSA-N 3-mercaptopropanoic acid Chemical compound OC(=O)CCS DKIDEFUBRARXTE-UHFFFAOYSA-N 0.000 claims description 9
- 239000003085 diluting agent Substances 0.000 claims description 9
- 125000003107 substituted aryl group Chemical group 0.000 claims 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 claims description 8
- 210000004899 c-terminal region Anatomy 0.000 claims description 8
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 8
- 206010006187 Breast cancer Diseases 0.000 claims description 7
- 208000026310 Breast neoplasm Diseases 0.000 claims description 7
- 208000005069 pulmonary fibrosis Diseases 0.000 claims description 7
- 238000011282 treatment Methods 0.000 claims description 7
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 claims description 6
- 206010009944 Colon cancer Diseases 0.000 claims description 6
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 6
- ODKSFYDXXFIFQN-SCSAIBSYSA-N D-arginine Chemical compound OC(=O)[C@H](N)CCCNC(N)=N ODKSFYDXXFIFQN-SCSAIBSYSA-N 0.000 claims description 6
- 201000010915 Glioblastoma multiforme Diseases 0.000 claims description 6
- 208000008839 Kidney Neoplasms Diseases 0.000 claims description 6
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 6
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 claims description 6
- 208000034578 Multiple myelomas Diseases 0.000 claims description 6
- 206010029260 Neuroblastoma Diseases 0.000 claims description 6
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 claims description 6
- 206010033128 Ovarian cancer Diseases 0.000 claims description 6
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 6
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 6
- 206010035226 Plasma cell myeloma Diseases 0.000 claims description 6
- 206010060862 Prostate cancer Diseases 0.000 claims description 6
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 6
- 206010038389 Renal cancer Diseases 0.000 claims description 6
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 claims description 6
- 239000000975 dye Substances 0.000 claims description 6
- 208000005017 glioblastoma Diseases 0.000 claims description 6
- 230000000155 isotopic effect Effects 0.000 claims description 6
- 201000010982 kidney cancer Diseases 0.000 claims description 6
- 201000005202 lung cancer Diseases 0.000 claims description 6
- 208000020816 lung neoplasm Diseases 0.000 claims description 6
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 6
- 201000001441 melanoma Diseases 0.000 claims description 6
- 201000002528 pancreatic cancer Diseases 0.000 claims description 6
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 6
- 125000004122 cyclic group Chemical group 0.000 claims description 5
- 239000002835 hiv fusion inhibitor Substances 0.000 claims description 5
- 229910052751 metal Inorganic materials 0.000 claims description 5
- 239000002184 metal Substances 0.000 claims description 5
- DLKUYSQUHXBYPB-NSSHGSRYSA-N (2s,4r)-4-[[2-[(1r,3r)-1-acetyloxy-4-methyl-3-[3-methylbutanoyloxymethyl-[(2s,3s)-3-methyl-2-[[(2r)-1-methylpiperidine-2-carbonyl]amino]pentanoyl]amino]pentyl]-1,3-thiazole-4-carbonyl]amino]-2-methyl-5-(4-methylphenyl)pentanoic acid Chemical compound N([C@@H]([C@@H](C)CC)C(=O)N(COC(=O)CC(C)C)[C@H](C[C@@H](OC(C)=O)C=1SC=C(N=1)C(=O)N[C@H](C[C@H](C)C(O)=O)CC=1C=CC(C)=CC=1)C(C)C)C(=O)[C@H]1CCCCN1C DLKUYSQUHXBYPB-NSSHGSRYSA-N 0.000 claims description 4
- 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 claims description 4
- FJHBVJOVLFPMQE-QFIPXVFZSA-N 7-Ethyl-10-Hydroxy-Camptothecin Chemical compound C1=C(O)C=C2C(CC)=C(CN3C(C4=C([C@@](C(=O)OC4)(O)CC)C=C33)=O)C3=NC2=C1 FJHBVJOVLFPMQE-QFIPXVFZSA-N 0.000 claims description 4
- 108010006654 Bleomycin Proteins 0.000 claims description 4
- WHUUTDBJXJRKMK-GSVOUGTGSA-N D-glutamic acid Chemical compound OC(=O)[C@H](N)CCC(O)=O WHUUTDBJXJRKMK-GSVOUGTGSA-N 0.000 claims description 4
- 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 claims description 4
- 229940122803 Vinca alkaloid Drugs 0.000 claims description 4
- IEDXPSOJFSVCKU-HOKPPMCLSA-N [4-[[(2S)-5-(carbamoylamino)-2-[[(2S)-2-[6-(2,5-dioxopyrrolidin-1-yl)hexanoylamino]-3-methylbutanoyl]amino]pentanoyl]amino]phenyl]methyl N-[(2S)-1-[[(2S)-1-[[(3R,4S,5S)-1-[(2S)-2-[(1R,2R)-3-[[(1S,2R)-1-hydroxy-1-phenylpropan-2-yl]amino]-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl]-3-methoxy-5-methyl-1-oxoheptan-4-yl]-methylamino]-3-methyl-1-oxobutan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]-N-methylcarbamate Chemical compound CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](C)[C@@H](O)c1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)C(=O)OCc1ccc(NC(=O)[C@H](CCCNC(N)=O)NC(=O)[C@@H](NC(=O)CCCCCN2C(=O)CCC2=O)C(C)C)cc1)C(C)C IEDXPSOJFSVCKU-HOKPPMCLSA-N 0.000 claims description 4
- HKGATZAPXCCEJR-OWRSNIELSA-N [4-[[(2s)-2-[[(2s)-2-[3-[2-[2-[2-[2-[2-[2-[2-[2-[3-(2,5-dioxopyrrol-1-yl)propanoylamino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]propanoylamino]-3-methylbutanoyl]amino]propanoyl]amino]phenyl]methyl (6s,6as)-3-[5-[[(6as)-2-methoxy-8-methyl-1 Chemical compound N([C@H](C(=O)N[C@@H](C)C(=O)NC1=CC=C(C=C1)COC(=O)N1C=2C=C(C(=CC=2C(=O)N2C=C(C)C[C@H]2[C@@H]1O)OC)OCCCCCOC1=CC2=C(C(N3C=C(C)C[C@H]3C=N2)=O)C=C1OC)C(C)C)C(=O)CCOCCOCCOCCOCCOCCOCCOCCOCCNC(=O)CCN1C(=O)C=CC1=O HKGATZAPXCCEJR-OWRSNIELSA-N 0.000 claims description 4
- 229960001561 bleomycin Drugs 0.000 claims description 4
- 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 claims 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 claims description 4
- 229960000975 daunorubicin Drugs 0.000 claims description 4
- 229960003668 docetaxel Drugs 0.000 claims description 4
- 229960004679 doxorubicin Drugs 0.000 claims description 4
- 238000001727 in vivo Methods 0.000 claims description 4
- 229960004768 irinotecan Drugs 0.000 claims description 4
- ANZJBCHSOXCCRQ-FKUXLPTCSA-N mertansine Chemical compound CO[C@@H]([C@@]1(O)C[C@H](OC(=O)N1)[C@@H](C)[C@@H]1O[C@@]1(C)[C@@H](OC(=O)[C@H](C)N(C)C(=O)CCS)CC(=O)N1C)\C=C\C=C(C)\CC2=CC(OC)=C(Cl)C1=C2 ANZJBCHSOXCCRQ-FKUXLPTCSA-N 0.000 claims description 4
- 229960005558 mertansine Drugs 0.000 claims description 4
- 108010093470 monomethyl auristatin E Proteins 0.000 claims description 4
- 229930184737 tubulysin Natural products 0.000 claims description 4
- 238000009007 Diagnostic Kit Methods 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 3
- 230000001588 bifunctional effect Effects 0.000 claims description 3
- HXCHCVDVKSCDHU-LULTVBGHSA-N calicheamicin Chemical compound C1[C@H](OC)[C@@H](NCC)CO[C@H]1O[C@H]1[C@H](O[C@@H]2C\3=C(NC(=O)OC)C(=O)C[C@](C/3=C/CSSSC)(O)C#C\C=C/C#C2)O[C@H](C)[C@@H](NO[C@@H]2O[C@H](C)[C@@H](SC(=O)C=3C(=C(OC)C(O[C@H]4[C@@H]([C@H](OC)[C@@H](O)[C@H](C)O4)O)=C(I)C=3C)OC)[C@@H](O)C2)[C@@H]1O HXCHCVDVKSCDHU-LULTVBGHSA-N 0.000 claims description 3
- 229930195731 calicheamicin Natural products 0.000 claims description 3
- 239000007850 fluorescent dye Substances 0.000 claims description 3
- 229960000303 topotecan Drugs 0.000 claims description 3
- VGIRNWJSIRVFRT-UHFFFAOYSA-N 2',7'-difluorofluorescein Chemical compound OC(=O)C1=CC=CC=C1C1=C2C=C(F)C(=O)C=C2OC2=CC(O)=C(F)C=C21 VGIRNWJSIRVFRT-UHFFFAOYSA-N 0.000 claims description 2
- OALHHIHQOFIMEF-UHFFFAOYSA-N 3',6'-dihydroxy-2',4',5',7'-tetraiodo-3h-spiro[2-benzofuran-1,9'-xanthene]-3-one Chemical compound O1C(=O)C2=CC=CC=C2C21C1=CC(I)=C(O)C(I)=C1OC1=C(I)C(O)=C(I)C=C21 OALHHIHQOFIMEF-UHFFFAOYSA-N 0.000 claims description 2
- 239000012099 Alexa Fluor family Substances 0.000 claims description 2
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 2
- LLUXQOVDMQZMPJ-KKUMJFAQSA-N Cys-Tyr-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CS)CC1=CC=C(O)C=C1 LLUXQOVDMQZMPJ-KKUMJFAQSA-N 0.000 claims description 2
- 229910052688 Gadolinium Inorganic materials 0.000 claims description 2
- GYHNNYVSQQEPJS-UHFFFAOYSA-N Gallium Chemical compound [Ga] GYHNNYVSQQEPJS-UHFFFAOYSA-N 0.000 claims description 2
- 108010078851 HIV Reverse Transcriptase Proteins 0.000 claims description 2
- 229940099797 HIV integrase inhibitor Drugs 0.000 claims description 2
- DBNGDEAQXGFGRA-ACRUOGEOSA-N Phe-Tyr-Lys Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CC2=CC=C(C=C2)O)C(=O)N[C@@H](CCCCN)C(=O)O)N DBNGDEAQXGFGRA-ACRUOGEOSA-N 0.000 claims description 2
- 229910052802 copper Inorganic materials 0.000 claims description 2
- 239000010949 copper Substances 0.000 claims description 2
- UIWYJDYFSGRHKR-UHFFFAOYSA-N gadolinium atom Chemical compound [Gd] UIWYJDYFSGRHKR-UHFFFAOYSA-N 0.000 claims description 2
- 229910052733 gallium Inorganic materials 0.000 claims description 2
- BEBCJVAWIBVWNZ-UHFFFAOYSA-N glycinamide Chemical group NCC(N)=O BEBCJVAWIBVWNZ-UHFFFAOYSA-N 0.000 claims description 2
- 239000001046 green dye Substances 0.000 claims description 2
- 239000003084 hiv integrase inhibitor Substances 0.000 claims description 2
- 239000004030 hiv protease inhibitor Substances 0.000 claims description 2
- 229910052738 indium Inorganic materials 0.000 claims description 2
- APFVFJFRJDLVQX-UHFFFAOYSA-N indium atom Chemical compound [In] APFVFJFRJDLVQX-UHFFFAOYSA-N 0.000 claims description 2
- 229910052702 rhenium Inorganic materials 0.000 claims description 2
- WUAPFZMCVAUBPE-UHFFFAOYSA-N rhenium atom Chemical compound [Re] WUAPFZMCVAUBPE-UHFFFAOYSA-N 0.000 claims description 2
- 239000001022 rhodamine dye Substances 0.000 claims description 2
- 239000003419 rna directed dna polymerase inhibitor Substances 0.000 claims description 2
- 229910052713 technetium Inorganic materials 0.000 claims description 2
- GKLVYJBZJHMRIY-UHFFFAOYSA-N technetium atom Chemical compound [Tc] GKLVYJBZJHMRIY-UHFFFAOYSA-N 0.000 claims description 2
- MPLHNVLQVRSVEE-UHFFFAOYSA-N texas red Chemical compound [O-]S(=O)(=O)C1=CC(S(Cl)(=O)=O)=CC=C1C(C1=CC=2CCCN3CCCC(C=23)=C1O1)=C2C1=C(CCC1)C3=[N+]1CCCC3=C2 MPLHNVLQVRSVEE-UHFFFAOYSA-N 0.000 claims description 2
- ANRHNWWPFJCPAZ-UHFFFAOYSA-M thionine Chemical compound [Cl-].C1=CC(N)=CC2=[S+]C3=CC(N)=CC=C3N=C21 ANRHNWWPFJCPAZ-UHFFFAOYSA-M 0.000 claims description 2
- 150000001945 cysteines Chemical class 0.000 claims 2
- UWKQSNNFCGGAFS-XIFFEERXSA-N irinotecan Chemical compound 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 UWKQSNNFCGGAFS-XIFFEERXSA-N 0.000 claims 2
- UCFGDBYHRUNTLO-QHCPKHFHSA-N topotecan Chemical compound C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UCFGDBYHRUNTLO-QHCPKHFHSA-N 0.000 claims 2
- 108010032976 Enfuvirtide Proteins 0.000 claims 1
- PEASPLKKXBYDKL-FXEVSJAOSA-N enfuvirtide Chemical compound C([C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(C)=O)[C@@H](C)O)[C@@H](C)CC)C1=CN=CN1 PEASPLKKXBYDKL-FXEVSJAOSA-N 0.000 claims 1
- 229960002062 enfuvirtide Drugs 0.000 claims 1
- 150000001413 amino acids Chemical class 0.000 abstract description 15
- 230000002018 overexpression Effects 0.000 abstract description 15
- 230000003827 upregulation Effects 0.000 abstract description 6
- 238000012377 drug delivery Methods 0.000 abstract description 5
- 208000026278 immune system disease Diseases 0.000 abstract description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 129
- 239000011347 resin Substances 0.000 description 86
- 229920005989 resin Polymers 0.000 description 86
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 74
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 64
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 57
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 36
- 238000003776 cleavage reaction Methods 0.000 description 34
- 230000007017 scission Effects 0.000 description 34
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 30
- 239000000243 solution Substances 0.000 description 30
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 27
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 27
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 26
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 24
- 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 20
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 20
- 238000002360 preparation method Methods 0.000 description 19
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 18
- 125000005647 linker group Chemical group 0.000 description 18
- 238000012360 testing method Methods 0.000 description 18
- 238000007363 ring formation reaction Methods 0.000 description 17
- 239000007787 solid Substances 0.000 description 16
- 230000004913 activation Effects 0.000 description 15
- 238000004949 mass spectrometry Methods 0.000 description 15
- 239000002904 solvent Substances 0.000 description 15
- 235000001014 amino acid Nutrition 0.000 description 14
- 230000021615 conjugation Effects 0.000 description 14
- 239000011541 reaction mixture Substances 0.000 description 14
- 239000000843 powder Substances 0.000 description 13
- 239000000047 product Substances 0.000 description 13
- LUGFCMICCJNLBC-VWLOTQADSA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-6-[(2-methylpropan-2-yl)oxycarbonyl-propan-2-ylamino]hexanoic acid Chemical compound C1=CC=C2C(COC(=O)N[C@@H](CCCCN(C(C)C)C(=O)OC(C)(C)C)C(O)=O)C3=CC=CC=C3C2=C1 LUGFCMICCJNLBC-VWLOTQADSA-N 0.000 description 12
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 12
- 238000010511 deprotection reaction Methods 0.000 description 12
- FEMOMIGRRWSMCU-UHFFFAOYSA-N ninhydrin Chemical compound C1=CC=C2C(=O)C(O)(O)C(=O)C2=C1 FEMOMIGRRWSMCU-UHFFFAOYSA-N 0.000 description 12
- 239000002244 precipitate Substances 0.000 description 12
- HNKJADCVZUBCPG-UHFFFAOYSA-N thioanisole Chemical compound CSC1=CC=CC=C1 HNKJADCVZUBCPG-UHFFFAOYSA-N 0.000 description 12
- LOBUWFUSGOYXQX-DHUJRADRSA-N (2r)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-3-[(4-methoxyphenyl)-diphenylmethyl]sulfanylpropanoic acid Chemical compound C1=CC(OC)=CC=C1C(C=1C=CC=CC=1)(C=1C=CC=CC=1)SC[C@@H](C(O)=O)NC(=O)OCC1C2=CC=CC=C2C2=CC=CC=C21 LOBUWFUSGOYXQX-DHUJRADRSA-N 0.000 description 11
- KLBPUVPNPAJWHZ-UMSFTDKQSA-N (2r)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-3-tritylsulfanylpropanoic acid Chemical compound C([C@@H](C(=O)O)NC(=O)OCC1C2=CC=CC=C2C2=CC=CC=C21)SC(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 KLBPUVPNPAJWHZ-UMSFTDKQSA-N 0.000 description 11
- 239000004480 active ingredient Substances 0.000 description 11
- 238000004128 high performance liquid chromatography Methods 0.000 description 11
- NDKDFTQNXLHCGO-UHFFFAOYSA-N 2-(9h-fluoren-9-ylmethoxycarbonylamino)acetic acid Chemical compound C1=CC=C2C(COC(=O)NCC(=O)O)C3=CC=CC=C3C2=C1 NDKDFTQNXLHCGO-UHFFFAOYSA-N 0.000 description 10
- 125000003277 amino group Chemical group 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 9
- 229920001223 polyethylene glycol Polymers 0.000 description 9
- 239000003826 tablet Substances 0.000 description 9
- 159000000021 acetate salts Chemical class 0.000 description 8
- 239000002775 capsule Substances 0.000 description 8
- 201000010099 disease Diseases 0.000 description 8
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 8
- 239000002552 dosage form Substances 0.000 description 8
- 229940079593 drug Drugs 0.000 description 8
- 238000009472 formulation Methods 0.000 description 8
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 7
- 238000005859 coupling reaction Methods 0.000 description 7
- 239000012467 final product Substances 0.000 description 7
- 239000007790 solid phase Substances 0.000 description 7
- JAUKCFULLJFBFN-VWLOTQADSA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-3-[4-[(2-methylpropan-2-yl)oxy]phenyl]propanoic acid Chemical compound C1=CC(OC(C)(C)C)=CC=C1C[C@@H](C(O)=O)NC(=O)OCC1C2=CC=CC=C2C2=CC=CC=C21 JAUKCFULLJFBFN-VWLOTQADSA-N 0.000 description 6
- JYUTZJVERLGMQZ-SANMLTNESA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-3-naphthalen-2-ylpropanoic acid Chemical compound C12=CC=CC=C2C2=CC=CC=C2C1COC(=O)N[C@H](C(=O)O)CC1=CC=C(C=CC=C2)C2=C1 JYUTZJVERLGMQZ-SANMLTNESA-N 0.000 description 6
- XXMFJKNOJSDQBM-UHFFFAOYSA-N 2,2,2-trifluoroacetic acid;hydrate Chemical compound [OH3+].[O-]C(=O)C(F)(F)F XXMFJKNOJSDQBM-UHFFFAOYSA-N 0.000 description 6
- 102000001189 Cyclic Peptides Human genes 0.000 description 6
- 108010069514 Cyclic Peptides Proteins 0.000 description 6
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical group NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- PMZXXNPJQYDFJX-UHFFFAOYSA-N acetonitrile;2,2,2-trifluoroacetic acid Chemical compound CC#N.OC(=O)C(F)(F)F PMZXXNPJQYDFJX-UHFFFAOYSA-N 0.000 description 6
- 238000005119 centrifugation Methods 0.000 description 6
- 239000000562 conjugate Substances 0.000 description 6
- 230000008878 coupling Effects 0.000 description 6
- 238000010168 coupling process Methods 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 230000007030 peptide scission Effects 0.000 description 6
- 239000012071 phase Substances 0.000 description 6
- 102000004196 processed proteins & peptides Human genes 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 6
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 6
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 5
- 102100021669 Stromal cell-derived factor 1 Human genes 0.000 description 5
- 230000021736 acetylation Effects 0.000 description 5
- 238000006640 acetylation reaction Methods 0.000 description 5
- 239000000969 carrier Substances 0.000 description 5
- 239000000839 emulsion Substances 0.000 description 5
- 230000006870 function Effects 0.000 description 5
- 230000014509 gene expression Effects 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 239000003381 stabilizer Substances 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- 230000001225 therapeutic effect Effects 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical class CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical group Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 4
- 239000002202 Polyethylene glycol Substances 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 4
- 238000012512 characterization method Methods 0.000 description 4
- 239000003086 colorant Substances 0.000 description 4
- 125000000151 cysteine group Chemical class N[C@@H](CS)C(=O)* 0.000 description 4
- 239000000796 flavoring agent Substances 0.000 description 4
- 239000007937 lozenge Substances 0.000 description 4
- 239000007921 spray Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 239000000375 suspending agent Substances 0.000 description 4
- 238000013268 sustained release Methods 0.000 description 4
- 239000002562 thickening agent Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 241000220479 Acacia Species 0.000 description 3
- 208000023275 Autoimmune disease Diseases 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- 239000001828 Gelatine Substances 0.000 description 3
- 101000617130 Homo sapiens Stromal cell-derived factor 1 Proteins 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 3
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 208000036142 Viral infection Diseases 0.000 description 3
- 239000002872 contrast media Substances 0.000 description 3
- 239000006071 cream Substances 0.000 description 3
- 238000003745 diagnosis Methods 0.000 description 3
- 239000002270 dispersing agent Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 229920000159 gelatin Polymers 0.000 description 3
- 235000019322 gelatine Nutrition 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 238000002595 magnetic resonance imaging Methods 0.000 description 3
- 239000012528 membrane Substances 0.000 description 3
- 238000012544 monitoring process Methods 0.000 description 3
- 238000002953 preparative HPLC Methods 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 239000000829 suppository Substances 0.000 description 3
- 239000012730 sustained-release form Substances 0.000 description 3
- 230000009385 viral infection Effects 0.000 description 3
- 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 2
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 2
- 241000416162 Astragalus gummifer Species 0.000 description 2
- 108010061299 CXCR4 Receptors Proteins 0.000 description 2
- 102000012000 CXCR4 Receptors Human genes 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-NJFSPNSNSA-N Carbon-14 Chemical compound [14C] OKTJSMMVPCPJKN-NJFSPNSNSA-N 0.000 description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
- 206010061818 Disease progression Diseases 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- UQSXHKLRYXJYBZ-UHFFFAOYSA-N Iron oxide Chemical compound [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 239000012901 Milli-Q water Substances 0.000 description 2
- 229920002472 Starch Polymers 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
- 229920001615 Tragacanth Polymers 0.000 description 2
- RHQDFWAXVIIEBN-UHFFFAOYSA-N Trifluoroethanol Chemical compound OCC(F)(F)F RHQDFWAXVIIEBN-UHFFFAOYSA-N 0.000 description 2
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 2
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 239000000443 aerosol Substances 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000007900 aqueous suspension Substances 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 239000003560 cancer drug Substances 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 230000012292 cell migration Effects 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 229940110456 cocoa butter Drugs 0.000 description 2
- 235000019868 cocoa butter Nutrition 0.000 description 2
- 230000005750 disease progression Effects 0.000 description 2
- 238000009510 drug design Methods 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- 235000019634 flavors Nutrition 0.000 description 2
- 125000005519 fluorenylmethyloxycarbonyl group Chemical group 0.000 description 2
- 235000013355 food flavoring agent Nutrition 0.000 description 2
- 238000004108 freeze drying Methods 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 229910052740 iodine Inorganic materials 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
- 239000008101 lactose Substances 0.000 description 2
- 235000010445 lecithin Nutrition 0.000 description 2
- 239000000787 lecithin Substances 0.000 description 2
- 229940067606 lecithin Drugs 0.000 description 2
- 239000006210 lotion Substances 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
- 239000000463 material Substances 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 229920000609 methyl cellulose Polymers 0.000 description 2
- 239000001923 methylcellulose Substances 0.000 description 2
- 235000010981 methylcellulose Nutrition 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 239000000178 monomer Substances 0.000 description 2
- 210000003928 nasal cavity Anatomy 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 238000010647 peptide synthesis reaction Methods 0.000 description 2
- 239000002953 phosphate buffered saline Substances 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- 229920006316 polyvinylpyrrolidine Polymers 0.000 description 2
- 239000013641 positive control Substances 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 239000000651 prodrug Substances 0.000 description 2
- 229940002612 prodrug Drugs 0.000 description 2
- 230000000069 prophylactic effect Effects 0.000 description 2
- 230000002441 reversible effect Effects 0.000 description 2
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 2
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 125000002653 sulfanylmethyl group Chemical group [H]SC([H])([H])[*] 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 150000003573 thiols Chemical class 0.000 description 2
- 238000011200 topical administration Methods 0.000 description 2
- 239000000196 tragacanth Substances 0.000 description 2
- 235000010487 tragacanth Nutrition 0.000 description 2
- 229940116362 tragacanth Drugs 0.000 description 2
- 229910052722 tritium Inorganic materials 0.000 description 2
- 239000003981 vehicle Substances 0.000 description 2
- SJVFAHZPLIXNDH-QFIPXVFZSA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-3-phenylpropanoic acid Chemical compound C([C@@H](C(=O)O)NC(=O)OCC1C2=CC=CC=C2C2=CC=CC=C21)C1=CC=CC=C1 SJVFAHZPLIXNDH-QFIPXVFZSA-N 0.000 description 1
- IYKLZBIWFXPUCS-VIFPVBQESA-N (2s)-2-(naphthalen-1-ylamino)propanoic acid Chemical compound C1=CC=C2C(N[C@@H](C)C(O)=O)=CC=CC2=C1 IYKLZBIWFXPUCS-VIFPVBQESA-N 0.000 description 1
- RWLSBXBFZHDHHX-VIFPVBQESA-N (2s)-2-(naphthalen-2-ylamino)propanoic acid Chemical compound C1=CC=CC2=CC(N[C@@H](C)C(O)=O)=CC=C21 RWLSBXBFZHDHHX-VIFPVBQESA-N 0.000 description 1
- ZORQXIQZAOLNGE-UHFFFAOYSA-N 1,1-difluorocyclohexane Chemical compound FC1(F)CCCCC1 ZORQXIQZAOLNGE-UHFFFAOYSA-N 0.000 description 1
- DDMOUSALMHHKOS-UHFFFAOYSA-N 1,2-dichloro-1,1,2,2-tetrafluoroethane Chemical compound FC(F)(Cl)C(F)(F)Cl DDMOUSALMHHKOS-UHFFFAOYSA-N 0.000 description 1
- VYMPLPIFKRHAAC-UHFFFAOYSA-N 1,2-ethanedithiol Chemical compound SCCS VYMPLPIFKRHAAC-UHFFFAOYSA-N 0.000 description 1
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 description 1
- AXTGDCSMTYGJND-UHFFFAOYSA-N 1-dodecylazepan-2-one Chemical compound CCCCCCCCCCCCN1CCCCCC1=O AXTGDCSMTYGJND-UHFFFAOYSA-N 0.000 description 1
- 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 1
- ZPDFIIGFYAHNSK-CTHHTMFSSA-K 2-[4,10-bis(carboxylatomethyl)-7-[(2r,3s)-1,3,4-trihydroxybutan-2-yl]-1,4,7,10-tetrazacyclododec-1-yl]acetate;gadolinium(3+) Chemical compound [Gd+3].OC[C@@H](O)[C@@H](CO)N1CCN(CC([O-])=O)CCN(CC([O-])=O)CCN(CC([O-])=O)CC1 ZPDFIIGFYAHNSK-CTHHTMFSSA-K 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical class OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- PCZHWPSNPWAQNF-LMOVPXPDSA-K 2-[[(2s)-2-[bis(carboxylatomethyl)amino]-3-(4-ethoxyphenyl)propyl]-[2-[bis(carboxylatomethyl)amino]ethyl]amino]acetate;gadolinium(3+);hydron Chemical compound [Gd+3].CCOC1=CC=C(C[C@@H](CN(CCN(CC(O)=O)CC([O-])=O)CC([O-])=O)N(CC(O)=O)CC([O-])=O)C=C1 PCZHWPSNPWAQNF-LMOVPXPDSA-K 0.000 description 1
- NFPWGFSRWDHFFT-UHFFFAOYSA-N 2-[bis[2-[carboxymethyl-[2-(methylamino)-2-oxoethyl]amino]ethyl]amino]acetic acid gadolinium Chemical compound [Gd].CNC(=O)CN(CCN(CCN(CC(O)=O)CC(=O)NC)CC(O)=O)CC(O)=O NFPWGFSRWDHFFT-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- JMTMSDXUXJISAY-UHFFFAOYSA-N 2H-benzotriazol-4-ol Chemical compound OC1=CC=CC2=C1N=NN2 JMTMSDXUXJISAY-UHFFFAOYSA-N 0.000 description 1
- ATAFDSCDEDHMOK-UHFFFAOYSA-N 3,3-diaminopropanoic acid Chemical compound NC(N)CC(O)=O ATAFDSCDEDHMOK-UHFFFAOYSA-N 0.000 description 1
- IUTPJBLLJJNPAJ-UHFFFAOYSA-N 3-(2,5-dioxopyrrol-1-yl)propanoic acid Chemical compound OC(=O)CCN1C(=O)C=CC1=O IUTPJBLLJJNPAJ-UHFFFAOYSA-N 0.000 description 1
- AUDYZXNUHIIGRB-UHFFFAOYSA-N 3-thiophen-2-ylpyrrole-2,5-dione Chemical compound O=C1NC(=O)C(C=2SC=CC=2)=C1 AUDYZXNUHIIGRB-UHFFFAOYSA-N 0.000 description 1
- OWSRLHPWDZOHCR-UHFFFAOYSA-N 4,4-diaminobutanoic acid Chemical compound NC(N)CCC(O)=O OWSRLHPWDZOHCR-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 description 1
- 229910000013 Ammonium bicarbonate Inorganic materials 0.000 description 1
- 208000005623 Carcinogenesis Diseases 0.000 description 1
- 108010008951 Chemokine CXCL12 Proteins 0.000 description 1
- 102000009410 Chemokine receptor Human genes 0.000 description 1
- 108050000299 Chemokine receptor Proteins 0.000 description 1
- 102000019034 Chemokines Human genes 0.000 description 1
- 108010012236 Chemokines Proteins 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- 239000004338 Dichlorodifluoromethane Substances 0.000 description 1
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 description 1
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 1
- 102000003688 G-Protein-Coupled Receptors Human genes 0.000 description 1
- 108090000045 G-Protein-Coupled Receptors Proteins 0.000 description 1
- 239000007821 HATU Substances 0.000 description 1
- 206010061218 Inflammation Diseases 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
- 102000018697 Membrane Proteins Human genes 0.000 description 1
- 108010052285 Membrane Proteins Proteins 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 229920000881 Modified starch Polymers 0.000 description 1
- HSHXDCVZWHOWCS-UHFFFAOYSA-N N'-hexadecylthiophene-2-carbohydrazide Chemical compound CCCCCCCCCCCCCCCCNNC(=O)c1cccs1 HSHXDCVZWHOWCS-UHFFFAOYSA-N 0.000 description 1
- 125000001429 N-terminal alpha-amino-acid group Chemical group 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
- FSXRLASFHBWESK-HOTGVXAUSA-N Phe-Tyr Chemical compound C([C@H](N)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(O)=O)C1=CC=CC=C1 FSXRLASFHBWESK-HOTGVXAUSA-N 0.000 description 1
- 101710088580 Stromal cell-derived factor 1 Proteins 0.000 description 1
- TUCNEACPLKLKNU-UHFFFAOYSA-N acetyl Chemical compound C[C]=O TUCNEACPLKLKNU-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 235000012538 ammonium bicarbonate Nutrition 0.000 description 1
- 239000001099 ammonium carbonate Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000033115 angiogenesis Effects 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 239000008135 aqueous vehicle Substances 0.000 description 1
- 235000021311 artificial sweeteners Nutrition 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000001363 autoimmune Effects 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 229920002988 biodegradable polymer Polymers 0.000 description 1
- 239000004621 biodegradable polymer Substances 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 125000005997 bromomethyl group Chemical group 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 230000036952 cancer formation Effects 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 229960004424 carbon dioxide Drugs 0.000 description 1
- 150000007942 carboxylates Chemical class 0.000 description 1
- 231100000504 carcinogenesis Toxicity 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 239000002576 chemokine receptor CXCR4 antagonist Substances 0.000 description 1
- KYKAJFCTULSVSH-UHFFFAOYSA-N chloro(fluoro)methane Chemical compound F[C]Cl KYKAJFCTULSVSH-UHFFFAOYSA-N 0.000 description 1
- 239000000306 component Substances 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 239000012084 conversion product Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 229940121384 cxc chemokine receptor type 4 (cxcr4) antagonist Drugs 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 description 1
- 235000019404 dichlorodifluoromethane Nutrition 0.000 description 1
- 229940042935 dichlorodifluoromethane Drugs 0.000 description 1
- 229940087091 dichlorotetrafluoroethane Drugs 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- BGRWYRAHAFMIBJ-UHFFFAOYSA-N diisopropylcarbodiimide Natural products CC(C)NC(=O)NC(C)C BGRWYRAHAFMIBJ-UHFFFAOYSA-N 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 229960001760 dimethyl sulfoxide Drugs 0.000 description 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 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
- 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 1
- 208000037765 diseases and disorders Diseases 0.000 description 1
- 239000002961 echo contrast media Substances 0.000 description 1
- 230000013020 embryo development Effects 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 239000002702 enteric coating Substances 0.000 description 1
- 238000009505 enteric coating Methods 0.000 description 1
- 210000002615 epidermis Anatomy 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 229960005191 ferric oxide Drugs 0.000 description 1
- KTWOOEGAPBSYNW-UHFFFAOYSA-N ferrocene Chemical compound [Fe+2].C=1C=C[CH-]C=1.C=1C=C[CH-]C=1 KTWOOEGAPBSYNW-UHFFFAOYSA-N 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- MXZROTBGJUUXID-UHFFFAOYSA-K gadobenic acid Chemical compound [H+].[H+].[Gd+3].[O-]C(=O)CN(CC([O-])=O)CCN(CC(=O)[O-])CCN(CC([O-])=O)C(C([O-])=O)COCC1=CC=CC=C1 MXZROTBGJUUXID-UHFFFAOYSA-K 0.000 description 1
- 229960003411 gadobutrol Drugs 0.000 description 1
- 229960005063 gadodiamide Drugs 0.000 description 1
- PIZALBORPSCYJU-QSQMUHTISA-H gadofosveset Chemical compound O.[Na+].[Na+].[Na+].[Gd+3].C1CC(OP([O-])(=O)OC[C@@H](CN(CCN(CC([O-])=O)CC([O-])=O)CC(=O)[O-])N(CC([O-])=O)CC([O-])=O)CCC1(C=1C=CC=CC=1)C1=CC=CC=C1 PIZALBORPSCYJU-QSQMUHTISA-H 0.000 description 1
- 229960003935 gadofosveset Drugs 0.000 description 1
- IZOOGPBRAOKZFK-UHFFFAOYSA-K gadopentetate Chemical compound [Gd+3].OC(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O IZOOGPBRAOKZFK-UHFFFAOYSA-K 0.000 description 1
- 229940005649 gadopentetate Drugs 0.000 description 1
- GFSTXYOTEVLASN-UHFFFAOYSA-K gadoteric acid Chemical compound [Gd+3].OC(=O)CN1CCN(CC([O-])=O)CCN(CC([O-])=O)CCN(CC([O-])=O)CC1 GFSTXYOTEVLASN-UHFFFAOYSA-K 0.000 description 1
- 229960005451 gadoteridol Drugs 0.000 description 1
- DPNNNPAKRZOSMO-UHFFFAOYSA-K gadoteridol Chemical compound [Gd+3].CC(O)CN1CCN(CC([O-])=O)CCN(CC([O-])=O)CCN(CC([O-])=O)CC1 DPNNNPAKRZOSMO-UHFFFAOYSA-K 0.000 description 1
- 229960002059 gadoversetamide Drugs 0.000 description 1
- 229940097926 gadoxetate Drugs 0.000 description 1
- 239000003349 gelling agent Substances 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 125000003827 glycol group Chemical group 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 125000004970 halomethyl group Chemical group 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 230000011132 hemopoiesis Effects 0.000 description 1
- 239000008240 homogeneous mixture Substances 0.000 description 1
- 102000053523 human CXCR4 Human genes 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000028709 inflammatory response Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 230000011268 leukocyte chemotaxis Effects 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 239000000314 lubricant 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
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 210000003071 memory t lymphocyte Anatomy 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- 230000001394 metastastic effect Effects 0.000 description 1
- 206010061289 metastatic neoplasm Diseases 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 235000019426 modified starch Nutrition 0.000 description 1
- 239000002324 mouth wash Substances 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- 235000021096 natural sweeteners Nutrition 0.000 description 1
- 230000009871 nonspecific binding Effects 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 238000011275 oncology therapy Methods 0.000 description 1
- 150000002895 organic esters Chemical class 0.000 description 1
- 229960003104 ornithine Drugs 0.000 description 1
- DRKHJSDSSUXYTE-UHFFFAOYSA-L oxidanium;2-[bis[2-[carboxylatomethyl-[2-(2-methoxyethylamino)-2-oxoethyl]amino]ethyl]amino]acetate;gadolinium(3+) Chemical compound [OH3+].[Gd+3].COCCNC(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CCN(CC([O-])=O)CC(=O)NCCOC DRKHJSDSSUXYTE-UHFFFAOYSA-L 0.000 description 1
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 235000010603 pastilles Nutrition 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 239000003961 penetration enhancing agent Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- PARWUHTVGZSQPD-UHFFFAOYSA-N phenylsilane Chemical compound [SiH3]C1=CC=CC=C1 PARWUHTVGZSQPD-UHFFFAOYSA-N 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 229920000747 poly(lactic acid) Polymers 0.000 description 1
- 239000004626 polylactic acid Substances 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 238000000159 protein binding assay Methods 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 229920002379 silicone rubber Polymers 0.000 description 1
- 239000004945 silicone rubber Substances 0.000 description 1
- 238000009097 single-agent therapy Methods 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000001593 sorbitan monooleate Substances 0.000 description 1
- 235000011069 sorbitan monooleate Nutrition 0.000 description 1
- 229940035049 sorbitan monooleate Drugs 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 210000000130 stem cell Anatomy 0.000 description 1
- 239000012609 strong anion exchange resin Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical group OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 230000008719 thickening Effects 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 238000012876 topography Methods 0.000 description 1
- 230000037317 transdermal delivery Effects 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- ZGYICYBLPGRURT-UHFFFAOYSA-N tri(propan-2-yl)silicon Chemical compound CC(C)[Si](C(C)C)C(C)C ZGYICYBLPGRURT-UHFFFAOYSA-N 0.000 description 1
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 description 1
- 229940029284 trichlorofluoromethane Drugs 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
- 210000004881 tumor cell Anatomy 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000011345 viscous material Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
Classifications
-
- 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
- C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
-
- 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
- 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
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0013—Luminescence
- A61K49/0017—Fluorescence in vivo
- A61K49/005—Fluorescence in vivo characterised by the carrier molecule carrying the fluorescent agent
- A61K49/0056—Peptides, proteins, polyamino acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
- A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
-
- 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
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
- C07K14/715—Receptors; Cell surface antigens; Cell surface determinants for cytokines; for lymphokines; for interferons
- C07K14/7158—Receptors; Cell surface antigens; Cell surface determinants for cytokines; for lymphokines; for interferons for chemokines
Definitions
- the present invention relates to a high affinity CXCR4 selective binding ligand peptide conjugate ("PC") of the Formula: P-(L-A) n (I) or a pharmaceutically acceptable salt thereof, and a method for using and producing the same.
- the high affinity CXCR4 selective binding ligand peptide conjugate of the invention are useful in diagnosing, treating or imaging a patient.
- each A is independently a diagnostic agent, a therapeutic agent, or an imaging agent;
- L is a linker or absent;
- P is a high affinity CXCR4 selective binding peptidyl ligand.
- the invention relates to a targeted drug delivery or imaging a patient or diagnosing a patient for a disease of which overexpression and/or upregulation of CXCR4 is implicated, such as cancers, HIV infection, and immune disorders.
- a targeted drug delivery or imaging a patient or diagnosing a patient for a disease of which overexpression and/or upregulation of CXCR4 is implicated such as cancers, HIV infection, and immune disorders.
- Compositions, kits and methods are disclosed herein for such uses.
- CXCL12 also called stromal cell-derived factor-1 or SDF-1
- CXCR4 a chemokine and chemokine receptor pair play important roles in hematopoiesis, multiple stages of tumorigenesis, and embryonic development
- CXCR4 activation of CXCR4 by CXCL12 has shown to direct leukocyte chemotaxis in the immune system in response to inflammation and progenitor cell migration during embryologic development.
- CXCR4 Activation of CXCR4 by CXCL12 has also been shown to mediate signaling pathway that is involved in breast cancer metastasis and memory T cell migration (Orimo, A., et al., Cell 2005, 121, 335-348).
- CXCR4 a G-protein-coupled receptor also known as fusin or CD 184 (cluster of differentiation 184), is constitutively- or over-expressed in a wide variety of human cancers, promoting local tumor cell proliferation, survival and angiogenesis (Huang, E.H., et al., J. Surg. Res. 2009, 155, 231-236). It has also been reported that CXCR4 is a co-receptor for HIV entry and infection of host cells and has been evaluated as a potential HIV therapy (Tamamura, H., et al., Biochem. Biophys. Res. Commun. 1998, 253, 877-882; Oberlin, E. et al., Nature, 1996, 382, 833-835).
- CXCR4 is overexpressed in numerous human cancers.
- CXCR4 antagonism has been shown to disrupt tumor-stromal interactions, sensitize cancer cells to cytotoxic drugs, and reduce tumor growth and metastatic burden.
- CXCR4 is a target not only for potential therapeutic intervention of cancer treatment, but also for noninvasive monitoring of disease progression, therapeutic guidance, and other diagnostic purposes (Chatterjee, S. et al., Adv Cancer Res. 2014; 124:31-82). Binding and Interacting with CXCR4 have been suggested as a potential way of targeted drug delivery (Wang, Y. et al., Curr PharmcolRep (2016) 2: 1-10).
- CXCR4 i.e., CXCR4 selective binding conjugate
- CXCR4 selective binding conjugate can have a wide variety uses including, but not limited to, in treating a wide array of clinical conditions associated with activation or over- expression of CXCR4, diagnosing a patient, and in mediacl imaging.
- the high affinity CXCR4 selective binding ligand peptide conjugate comprises a peptidyl moiety that has a high affinity for selectively binding to CXCR4 which is linked or attached to (optionally via a linker) to an active component.
- the active component can be a diagnostic agent, a therapeutic agent, or an imaging agent. In this manner, the peptidyl moiety selectively binds to CXCR4 receptor and delivers the active component.
- the high affinity CXCR4 selective binding ligand peptide conjugate is a compound of the Formula:
- n is an integer from 1 to the total number of amino acid residue within P that have a side-chain functional group;
- P is a high affinity CXCR4 selective binding peptide moiety;
- each L is independently an optional linker (i.e., it can be absent or be a linker such as polyethylene glycol moiety or other linkers known to one skilled in the art);
- each A is independently an active component such as a diagnostic agent, a therapeutic agent, or an imaging agent. While it is readily apparent to those skilled in the art, it should be noted that when L is absent, A is attached directly to P, e.g., through a chemical bond, such as an amide bond or an ester bond.
- compound of Formula I is used in diagnosis of or treatment of a clinical condition associated with overexpression or upregulation of CXCR4, i.e., A is a diagnostic agent or a drug.
- compound of Formula I includes (i) a peptidyl ligand (i.e., a peptide moiety) that has a high affinity to CXCR4, (2) optionally a linker, and (3) an active component, e.g., a diagnostic agent, a therapeutic agent (e.g., a drug), or an imaging agent (e.g., a radioactive moiety, a fluorescent moiety, etc.).
- moiety P i.e., a high affinity CXCR4 selective bindign petide moiety
- a is 0 or 1
- AA 1 along with the sulfur atom that is attached thereto is 3-mercaptopropionic acid, optionally substituted cysteine, or optionally substituted
- Ar 1 is an optionally substituted aryl
- X 1 is Arg, Dap, Dab, Orn, Lys, Dap(iPr), Dab(iPr), Orn(iPr), or Lys(iPr);
- X 2 is Arg, Dap, Dab, Orn, Lys, Dap(iPr), Dab(iPr), Orn(iPr), Lys(iPr), D-Arg, D-
- X 3 is Lys, Gly or absent;
- X 4 is Lys, Phe, 2Nal, INal, the D -isomer thereof, Gly, or absent;
- X 5 is Lys, Gly or absent
- R 2 is -OR 4 or - HR 5 , wherein R 4 and R 5 are H, alkyl, optionally substituted aryl or optionally substituted aralkyl.
- optional linker and moiety A i.e., -L-A moiety
- Formula I can be attached to any of the amino acids via a functional group that is present in the side-chain thereof.
- a is 0 or 1
- AA 1 along with the sulfur atom that is attached thereto is 3-mercaptopropionic acid, optionally substituted cysteine, or optionally substituted homocysteine;
- AA 2 along with the sulfur atom that is attached thereto is cysteine or homocysteine;
- Ar 1 is an optionally substituted aryl;
- X 1 is Arg, Dap, Dab, Orn, Lys, Dap(iPr), Dab(iPr), Orn(iPr), or Lys(iPr);
- X 2 is Arg, Dap, Dab, Orn, Lys, Dap(iPr), Dab(iPr), Orn(iPr), Lys(iPr), D-Arg, D-Dap, D-
- Another aspect of the invention provides a diagnostic kit comprising a high affinity CXCR4 selective binding ligand peptide conjugate disclosed herein, e.g., a compound of Formula I where A is a diagnostic agent.
- Yet another aspect of the invention provides a composition comprising (i) a high affinity CXCR4 selective binding ligand peptide conjugate disclosed herein and (ii) a pharmaceutically acceptable carrier, diluent, excipient or a combination thereof.
- Still another aspect of the invention provides a method for imaging cancer cells in a patient. Such a method generally includes administering to a patient an imaging effective amount of a high affinity CXCR4 selective binding ligand peptide conjugate of the invention, e.g., compound of Formula I where A is an imaging agent; and imaging cancer cells in said patient using an imaging apparatus.
- Yet other aspects of the invention provide a method for treating cancer in a patient by administering a therapeutically effective amount of a pharmaceutical composition that includes a compound of Formula I, where A is a therapeutic agent for cancer (i.e., a cancer or oncology drug).
- A is a therapeutic agent for cancer (i.e., a cancer or oncology drug).
- a of compound of Formula I is a diagnostic agent or an imaging agent
- compounds of the invention can be used in a diagnostic or an imaging kit, respectively.
- compound of Formula I is used in treating a patient suffering from rheumatoid arthritis, pulmonary fibrosis, HIV infection, or a cancer.
- the method includes administering a therapeutically effective amount of a compound of Formula I (where A is a therapeutic agent for treating rheumatoid arthritis, pulmonary fibrosis, HIV infection, or a cancer, respectively) to a patient in need of such a treatment.
- Typical cancer that is treated with a compound of Formula I includes, but are not limited to, breast cancer, pancreatic cancer, melanoma, prostate cancer, kidney cancer, neuroblastoma, non-Hodgkin's lymphoma, lung cancer, ovarian cancer, colorectal cancer, multiple myeloma, glioblastoma multiforme, and chronic lymphocytic leukemia.
- Another aspect of the invention provides a method for targeted drug delivery for a clinical condition associated with overexpression and/or upregulation of CXCR4.
- exemplary clinical conditions include, but are not limited to, rheumatoid arthritis, pulmonary fibrosis, HIV infection, and cancer.
- Specific examples of cancers include breast cancer, pancreatic cancer, melanoma, prostate cancer, kidney cancer, neuroblastoma, non-Hodgkin's lymphoma, lung cancer, ovarian cancer, colorectal cancer, multiple myeloma, glioblastoma multiforme, and chronic lymphocytic leukemia.
- Another aspect of the invention provides a method for disease diagnosis and monitoring for a clinical condition associated with overexpression and/or upregulation of CXCR4.
- exemplary clinical conditions include, but are not limited to, rheumatoid arthritis, pulmonary fibrosis, HIV infection, and cancer.
- Specific examples of cancers include breast cancer, pancreatic cancer, melanoma, prostate cancer, kidney cancer, neuroblastoma, non- Hodgkin's lymphoma, lung cancer, ovarian cancer, colorectal cancer, multiple myeloma, glioblastoma multiforme, and chronic lymphocytic leukemia.
- exemplary clinical conditions include, but are not limited to, rheumatoid arthritis, pulmonary fibrosis, HIV infection, and cancer.
- Specific examples of cancers include breast cancer, pancreatic cancer, melanoma, prostate cancer, kidney cancer, neuroblastoma, non- Hodgkin's lymphoma, lung cancer, ovarian cancer, colorectal cancer, multiple myeloma, glioblastoma multiforme, and chronic lymphocytic leukemia.
- CXCR4 plays an important role in immune and inflammatory responses in various diseases and disorders, including cancer, viral infections, as well as autoimmune pathologies such as rheumatoid arthritis.
- the present invention is based at least in part on reducing or preventing overexpression or activation of CXCR4 to treat, diagnose or image a clinical condition associated with CXCR4 overexpression and/or activation.
- overexpression and/or activation refers to expression of a gene above its normal (i.e., control) or baseline level and/or activation of CXCR4 above its normal, control or baseline level, respectively.
- normal baseline level
- control level refers to expression and/or activity level of CXCR4 in subject(s) that do not have a disease or a clinical condition associated with overexpression and/or activation of CXCR4, such as those disclosed herein.
- the baseline level can be a normal level, meaning the level in a sample from a normal subject that do not have a clinical condition associated with overexpression and/or activation (or activity) of CXCR4.
- the overexpression and/or activation of CXCR4 can also be determined by comparing the sample result with a positive control.
- the term "positive control” as used herein refers to a level of CXCR4 expression and/or activation (or activity) established in a sample from a subject or from a population of individuals, where the sample was believed, based on data from that sample, to have a disease or a clinical condition associated with overexpression and/or activation of CXCR4 (e.g., cancer, autoimmune disease such as rheumatoid arthritis and viral infection, such as HIV infection).
- a disease or a clinical condition associated with overexpression and/or activation of CXCR4 e.g., cancer, autoimmune disease such as rheumatoid arthritis and viral infection, such as HIV infection.
- the baseline level can be established from a previous sample from the subject being tested, so that the disease progression or regression of the subject can be monitored over time and/or the efficacy of treatment can be evaluated.
- Some aspects of the invention provide compounds that have a high affinity toward
- CXCR4 that is attached to a diagnostic agent, a therapeutic agent or an imaging agent, optionally through a linker.
- Such compounds include a CXCR4 binding moiety and an active component.
- the invention also provides methods for using the same, e.g., in targeted delivery of therapeutics to treat clinical conditions manifested by or associated with overexpression and/or activation of CXCR4.
- the term "high affinity" means the compound or the moiety that binds to CXCR4 has a binding constant (3 ⁇ 4) of about 10 nM or less, typically about 3 nM or less, and often 1 nM or less.
- high affinity means the compound or the moiety that binds to CXCR4 has 50% binding inhibition concentration (IC 50 ) of about 30 nM or less, typically about 10 nM or less and often about 3 nM or less.
- IC 50 binding inhibition concentration
- a high affinity CXCR4 selective binding ligand peptide conjugate is of the Formula:
- n is an integer from 1 to the sum of (the total number of amino acids in P and the total number of side-chain functional group), typically n is 1 to the number of amino acids in P, or n is 1 to the number of amino acids in P that have a side-chain with a functional group, often n is an integer of 1 to 5, more often n is an integer from 1 to 3;
- A is one or more diagnostic agents, a therapeutic agents, or imaging agents
- each L is independently a bifunctional linker or absent;
- A is attached to P, e.g., through a chemical bond, such as an amide bond or an ester bond; and
- P is a high affinity CXCR4 selective binding peptidyl ligand (i.e., a peptide moiety that selectively binds to CXCR4).
- n is an integer from 1 to the sum of (the total number of amino acids in P and the total number of side-chain functional group).
- n is an integer from 1 to 7, often from 1 to 5, more often from 1 to 3 and most often 1 or 2.
- n can be an integer from 1 to 9 (7 amino acid residue of P + 2 side-chain functional groups). In this manner, all of the functional groups of P can be attached to -L-A moiety.
- the moiety A in compound of Formula I can be attached to any portion of the P moiety. Typically, A moiety is attached to the N-terminal end or the C-terminal end of said peptide (the P moiety), or to a function group that is present on the side-chain of the amino acid residue of said peptide, or a combination of any one of the positions thereof. In some embodiments, compound of Formula I has a plurality of A moieties.
- P is a high affinity CXCR4 binding peptidyl of the
- a is 0 or 1 ;
- AA 1 along with the sulfur atom that is attached thereto is 3-mercaptopropionic acid, optionally substituted cysteine, or optionally substituted
- Ar 1 is an optionally substituted aryl
- X 1 is Arg, Dap, Dab, Orn, Lys, Dap(iPr), Dab(iPr), Orn(iPr), or Lys(iPr);
- X 2 is Arg, Dap, Dab, Orn, Lys, Dap(iPr), Dab(iPr), Orn(iPr), Lys(iPr), D-Arg, D-
- X 3 is Lys, Gly or absent
- X 4 is Lys, Phe, 2Nal, INal, the D -isomer thereof, Gly, or absent;
- X 5 is Lys, Gly or absent
- R 2 is -OR 4 or - HR 5 , wherein R 4 and R 5 are H, alkyl, optionally substituted aryl, or optionally substituted aralkyl.
- Moiety -L-A of Compound of Formula I can be attached to AA 1 (e.g., to a-amino group of cysteine or homocysteine) and/or R 4 and/or R 5 , or R 4 and R 5 can be -L-A, where L is optionally a linker and A is a therapeutic agent, a diagnostic agent, or an imaging agent. Still further the moiety -L-A can be attached to the a-amino group of the N-terminal amino acid or a functional group of the side-chain of any of the amino acids of the peptidyl moiety.
- A is an imaging agent.
- 45 ⁇ useful imaging agent of the invention includes a positron-emitting radioisotope such CI, "Ti 51 Mn, 61 Cu, 6 Zn, 68 Ga, U C, 1 N, 15 0, and 18 F.
- a positron-emitting radioisotope such as, "Ti 51 Mn, 61 Cu, 6 Zn, 68 Ga, U C, 1 N, 15 0, and 18 F.
- the positron-emitting radioisotope is attached to the linker or as a part of the linker (L moiety).
- a useful imaging agent includes a radioactive metal isotope that is coordinated (i.e., chelated) to a chelating group.
- Particularly useful radioactive metal isotope include technetium, rhenium, gallium, gadolinium, indium, copper and a combination thereof.
- Appropriate chelating groups for a particular radioactive metal isotope are well known to one skilled in the art. For example, ferrocene and its derivatives, ethylenediaminetetraacetic acid (“EDTA”), its derivatives, a peptidyl moiety Dap-Asp-Cys and its derivatives (see U.S. Pat. No. 7, 128,893), and others known in the art.
- Yet another example of a useful imaging agent includes a contrasting agent.
- Contrasting agents are widely used, for example, in magnetic resonance imaging (MRI).
- MRI magnetic resonance imaging
- contrasting agents are known to one skilled in the art including gadobenate, gadobutrol, gadodiamide, gadofosveset, gadopentetate, gadoterate, gadoteridol,
- gadoversetamide gadoxetate, and iron oxide.
- Still another example of a useful imaging agent includes a fluorescent dye, such as fluorenylmethyloxycarbonyl (FMOC) and its derivatives, an AlexaFluor dye, an Oregon Green dye, a fluoresceins, a BODIPY (boron-dipyrromethene) dye, a cyanine dye, a rhodamine dye, a DyLight dye, and Texas Red.
- a fluorescent dye such as fluorenylmethyloxycarbonyl (FMOC) and its derivatives, an AlexaFluor dye, an Oregon Green dye, a fluoresceins, a BODIPY (boron-dipyrromethene) dye, a cyanine dye, a rhodamine dye, a DyLight dye, and Texas Red.
- A is a diagnostic agent.
- diagnostic agents that can be used in compound of the invention include an imaging agent, an isotopic agent, or a radioactive agent.
- linker L comprises a functional group that is capable of releasing A in vivo.
- Suitable functional groups that is capable of releasing A depends on the nature of the function group on moiety A that is linked to the linker.
- the functional group on L can be a carboxylate such that an ester bond or an amide bond, respectively, is formed between A and L.
- the corresponding functional group on L can be a hydroxyl group or an amino group to form an ester bond or an amide bond, respectively.
- Other suitable functional groups on L that is capable releasing A in vivo are well known to one skilled in the art including a disulfide bond linkage, an ester linkage, a thiol-maleimide linkage, and the like.
- A is a therapeutic agent.
- Suitable therapeutic agents include those that are known to one skilled in the art for treatment of cancer, autoimmune disease (e.g., rheumatoid arthritis), viral infection (e.g., HIV infection), etc.
- Exemplary therapeutic agents that are useful in compounds of the invention include, but are not limited to, bleomycin, daunorubicin, doxorubicin, docetaxel, irinotecan, monomethyl auristatin E, mertansine, paclitaxel, SN-38, tesirine, tubulysin, vinca alkaloids, and an analog or derivative thereof, HIV protease inhibitors, HIV fusion inhibitors, HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV entry inhibitors, and therapeutics for autoimmune diseases.
- High affinity CXCR4 selective binding ligand peptide conjugates of the invention include, but are not limited to:
- R a is acetyl-, acetyl-Cys(S-paclitaxel)-, or acetyl-Cys(S-paclitaxel)-(mini-PEG6)-; and R b is glycyl-amide, glycyl-Cys(S-paclitaxel)-amide, or (mini-PEG6)-Cys(S-paclitaxel)- amide,
- R a or R b comprises S-paclitaxel.
- compounds of the invention are of the Formula:
- a is 0 or 1
- AA 1 along with the sulfur atom that is attached thereto is 3-mercaptopropionic acid, optionally substituted cysteine, or optionally substituted homocysteine, wherein A is optionally attached to a-amino group of said cysteine or homocysteine;
- Ar 1 is an optionally substituted aryl
- X 1 is Arg, Dap, Dab, Orn, Lys, Dap(iPr), Dab(iPr), Orn(iPr), or Lys(iPr);
- X 2 is Arg, Dap, Dab, Orn, Lys, Dap(iPr), Dab(iPr), Orn(iPr), Lys(iPr), D-Arg, D-Dap, D-
- L is optionally a linker
- A is a therapeutic agent, a diagnostic agent or an imaging agent.
- a is 0. Still in other instances, a is
- AA 1 together with the sulfur atom that is attached thereto is 3- mercaptopropionic acid. Still yet in other instances, AA 1 together with the sulfur atom that is attached thereto is cysteine. In other instances, AA 1 together with the sulfur atom that is attached thereto is homocysteine.
- AA 2 together with the sulfur atom that is attached thereto is cysteine. In yet other embodiments, AA 2 together with the sulfur atom that is attached thereto is homocysteine.
- a in compounds of Formula III is an imaging agent.
- a in compounds of Formula III is a therapeutic agent.
- Exemplary therapeutic agents within compounds of Formula III include, but are not limited to, bleomycin, calicheamicin, daunorubicin, docetaxel, doxorubicin, irinotecan, mertansine, monomethyl auristatin E, paclitaxel, SN-38, tesirine, topotecan, tubulysin, vinca alkaloids, and an analog or derivative thereof, and a combination thereof.
- L can be any biocompatible bifunctional linker such as polyethylene glycol
- PEG polyamino acid
- m is an integer from 0 to 100, typically 1 to 50, often 1 to 25, and more often 1 to 10.
- L is a polymer (e.g., PEG, PAA)
- the total number of monomer within the chain is from about 1 (i.e., a monomer) to about 20, typically from about 1 to about 10, and often from about 1 to 6.
- a in compounds of Formula III is a diagnostic agent, such as a radioactive agent, fluorescent agent, etc.
- imaging agents are well known to one skilled in the art.
- contrast agents for magnetic resonance imaging agents, ultrasound contrast agents, and radio contrast agents See, for example, en.wikipedia.org/wiki/ Contrast agent.
- Another aspect of the invention provides a diagnostic kit comprising a high affinity CXCR4 selective binding ligand peptide conjugate described herein where A of compound of Formula I is a diagnostic agent.
- compositions comprising a compound of Formula I and a pharmaceutically acceptable carrier.
- Pharmaceutically acceptable carrier can include a diluent, an excipient, a flavoring agent, an adjuvant, a binder, a stabilizer, coloring agent, or a combination thereof.
- pharmaceutically acceptable carrier refers to any excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes excipient that is acceptable for veterinary use as well as human pharmaceutical use.
- the present invention includes pharmaceutical compositions comprising at least one compound of the invention, or an individual isomer, racemic or non-racemic mixture of isomers or a pharmaceutically acceptable salt or solvate thereof, together with at least one pharmaceutically acceptable carrier, and optionally other therapeutic and/or prophylactic ingredients.
- the compounds of the invention are administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similar utilities.
- Suitable dosage ranges are typically 1-500 mg daily, typically 1-100 mg daily, and often 1-30 mg daily, depending on numerous factors such as the severity of the disease to be treated, the age and relative health of the subject, the potency of the compound used, the route and form of administration, the indication towards which the administration is directed, and the preferences and experience of the medical practitioner involved.
- One of ordinary skill in the art of treating such diseases is typically able, without undue experimentation and in reliance upon personal knowledge and the disclosure of this application, to ascertain a therapeutically effective amount of the compounds of the invention.
- compounds of the invention are administered as pharmaceutical formulations including those suitable for oral (including buccal and sub-lingual), rectal, nasal, topical, pulmonary, vaginal, or parenteral (including intramuscular, intraarterial, intrathecal, subcutaneous and intravenous) administration or in a form suitable for administration by inhalation or insufflation.
- Typical manner of administration is generally oral using a convenient daily dosage regimen which can be adjusted according to the degree of affliction.
- a compound or compounds of the invention, together with one or more conventional adjuvants, carriers, or diluents, can be placed into the form of pharmaceutical compositions and unit dosages.
- the pharmaceutical compositions and unit dosage forms can be comprised of conventional ingredients in conventional proportions, with or without additional active compounds or principles, and the unit dosage forms can contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed.
- compositions can be employed as solids, such as tablets or filled capsules, semisolids, powders, sustained release formulations, or liquids such as solutions, suspensions, emulsions, elixirs, or filled capsules for oral use; or in the form of suppositories for rectal or vaginal administration; or in the form of sterile injectable solutions for parenteral use.
- Formulations containing about one (1) milligram of active ingredient or, more broadly, about 0.01 to about one hundred (100) milligrams, per tablet, are accordingly suitable representative unit dosage forms.
- the compounds of the invention can be formulated in a wide variety of oral administration dosage forms.
- the pharmaceutical compositions and dosage forms can comprise a compound or compounds of the invention or pharmaceutically acceptable salts thereof as the active component.
- the pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules.
- a solid carrier can be one or more substances which can also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.
- the carrier In powders, the carrier generally is a finely divided solid which is a mixture with the finely divided active component.
- the active component In tablets, the active component generally is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired.
- the powders and tablets preferably contain from about one (1) to about seventy (70) percent of the active compound.
- Suitable carriers include but are not limited to magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatine, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like.
- the term "preparation" is intended to include the formulation of the active compound with encapsulating material as carrier, providing a capsule in which the active component, with or without carriers, is surrounded by a carrier, which is in association with it.
- cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be as solid forms suitable for oral administration.
- liquid form preparations including emulsions, syrups, elixirs, aqueous solutions, aqueous suspensions, or solid form preparations which are intended to be converted shortly before use to liquid form preparations.
- Emulsions can be prepared in solutions, for example, in aqueous propylene glycol solutions or may contain emulsifying agents, for example, such as lecithin, sorbitan monooleate, or acacia.
- Aqueous solutions can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizers, and thickening agents.
- Aqueous suspensions can be prepared by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well known suspending agents.
- Solid form preparations include solutions, suspensions, and emulsions, and can contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.
- the compounds of the invention can also be formulated for parenteral
- compositions can take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, for example solutions in aqueous polyethylene glycol.
- oily or nonaqueous carriers, diluents, solvents or vehicles examples include propylene glycol, polyethylene glycol, vegetable oils (e.g., olive oil), and injectable organic esters (e.g., ethyl oleate), and can contain formulatory agents such as preserving, wetting, emulsifying or suspending, stabilizing and/or dispersing agents.
- the active ingredient can be in powder form, obtained by aseptic isolation of sterile solid or by lyophilization from solution for constitution before use with a suitable vehicle, e.g., sterile, pyrogen-free water.
- a suitable vehicle e.g., sterile, pyrogen-free water.
- the compounds of the invention can be formulated for topical administration to the epidermis as ointments, creams or lotions, or as a transdermal patch.
- Ointments and creams can, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents.
- Lotions can be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents.
- Formulations suitable for topical administration in the mouth include lozenges comprising active agents in a flavored base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatine and glycerine or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
- the compounds of the invention can be formulated for administration as suppositories.
- a low melting wax such as a mixture of fatty acid glycerides or cocoa butter is first melted and the active component is dispersed homogeneously, for example, by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and to solidify.
- the compounds of the invention can also be formulated for vaginal administration. Pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
- the compounds of the invention can be formulated for nasal administration.
- the solutions or suspensions are applied directly to the nasal cavity by conventional means, for example, with a dropper, pipette or spray.
- the formulations can be provided in a single or multidose form. In the latter case of a dropper or pipette, this can be achieved by the patient administering an appropriate, predetermined volume of the solution or suspension. In the case of a spray, this can be achieved for example by means of a metering atomizing spray pump.
- the compounds of the invention can be formulated for aerosol administration, particularly to the respiratory tract and including intranasal administration.
- the compound will generally have a small particle size for example of the order of five (5) microns or less. Such a particle size can be obtained by means known in the art, for example by micronization.
- the active ingredient is provided in a pressurized pack with a suitable propellant such as a chlorofluorocarbon (CFC), for example, dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, or carbon dioxide or other suitable gas.
- CFC chlorofluorocarbon
- the aerosol can conveniently also contain a surfactant such as lecithin.
- the dose of drug can be controlled by a metered valve.
- the active ingredients can be provided in a form of a dry powder, for example, a powder mix of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidine (PVP).
- a powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidine (PVP).
- the powder carrier typically forms a gel in the nasal cavity.
- the powder composition can be presented in unit dose form, for example, in capsules or cartridges of e.g., gelatine or blister packs from which the powder can be administered by means of an inhaler.
- formulations can be prepared with enteric coatings adapted for sustained or controlled release administration of the active ingredient.
- the compounds of the invention can be formulated in transdermal or subcutaneous drug delivery devices. These delivery systems are advantageous when sustained release of the compound is necessary or desired and when patient compliance with a treatment regimen is crucial.
- Compounds in transdermal delivery systems are frequently attached to a skin-adhesive solid support.
- the compound of interest can also be combined with a penetration enhancer, e.g., Azone (l-dodecylazacycloheptan-2-one).
- Azone l-dodecylazacycloheptan-2-one
- Sustained release delivery systems can be inserted subcutaneously into the subdermal layer by surgery or injection.
- the subdermal implants encapsulate the compound in a lipid soluble membrane, e.g., silicone rubber, or a biodegradable polymer, e.g., polylactic acid.
- the pharmaceutical preparations are typically in unit dosage forms.
- the preparation is often subdivided into unit doses containing appropriate quantities of the active component.
- the unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules.
- the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
- compositions which include therapeutically effective mounts of compounds of Formula I or pharmaceutically acceptable salts thereof or a prodrug thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.
- the term refers to combined amounts of the active ingredients that result in the therapeutic effect, whether administered in combination, serially, or simultaneously.
- the compounds of Formula I and pharmaceutically acceptable salts thereof are as described above.
- the carrier(s), diluent(s), or excipient(s) must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
- a process for the preparation of a pharmaceutical formulation including admixing a compound of Formula I, or a pharmaceutically acceptable salt thereof or a prodrug thereof, with one or more pharmaceutically acceptable carriers, diluents, or excipients.
- compositions of this disclosure comprise a combination of a compound of the present disclosure and one or more additional therapeutic or prophylactic agent
- both the compound and the additional agent are usually present at dosage levels of between about 10 to 150%, and more typically between about 10 and 80% of the dosage normally administered in a monotherapy regimen.
- Still another aspect of the invention provides a method for imaging cancer cells in a patient comprising administering to a patient an imaging effective amount of a high affinity CXCR4 selective binding ligand peptide conjugate of Formula I, where A is an imaging agent, and imaging cancer cells in said patient using an imaging apparatus.
- the imaging apparatus used depends on the nature of imaging agent A of compound of Formula I. For example, if A is a positron-emitting radioisotope, then the imaging apparatus used is a PET scan, and when A is a contrasting agent, then the imaging apparatus can be a computed topography apparatus or an MRI apparatus. When A is a radioactive isotope, the imaging apparatus can be an x-ray machine or other similar device.
- One particular aspect of the invention provides a method for treating cancer in a patient.
- the method comprises administering a therapeutically effective amount of a compound of Formula I (where A is a cancer drug) or a pharmaceutical composition comprising a compound of Formula I (where A is a cancer drug) to a cancer patient.
- Another particular aspect of the invention provides a diagnostic or an imaging kit comprising a high affinity CXCR4 selective binding ligand peptide conjugate (PC) of Formula I, where A is a diagnostic agent or an imaging agent, respectively.
- PC selective binding ligand peptide conjugate
- Still another particular aspect of the invention provides a method for treating a patient suffering from rheumatoid arthritis, pulmonary fibrosis, HIV infection, or a cancer.
- the method includes administering a therapeutically effective amount of a compound of Formula I to a patient in need of treatment thereof.
- a of compound of Formula I is a therapeutic agent that can be used to treat the particular clinical condition to be treated.
- BOP (benzotriazol-l-yloxy)-tris(dimethylamino) phosphonium hexafluorophosphate
- Bz (benzotriazol-l-yloxy)-tris(dimethylamino) phosphonium hexafluorophosphate
- hydroxybenzotriazole hCys: homocysteine; iPr: isopropyl; IPA: isopropyl alcohol; Me: methyl; Mmt: 4-mthoxytrityl; Mpa: 3-mercaptopropionic acid; 2Nal: 2-naphthylalanine; INal: 1- naphthylalanine; NMM: N-methylmorpholine; NMP: N-methyl-pyrrolidone; Orn: ornithine; Pbf: 2,2,4,6,7-pentamethyl-dihydrobenzofurane-5-sulfonyl; PBS: phosphate buffered saline; PyBOP: (benzotriazol-l-yloxy)-tris(pyrrolidino)-phosphonium hexafluoro-phosphate; PyBrOP: bromotris(pyrrolidino)phosphonium hexafluorophosphate; tBu: ter
- Peptides were synthesized using solid phase peptide synthesis chemistry known in the art.
- the cyclic structure of those peptides was established, for a disulfide, by using air oxidation, or iodine oxidation in the presence of acidic acid, or for a bisthioether ring, by nucleophilic substitution using a bis(halomethyl) aryl compound, typically using 1.3 equivalents of a bis(bromom ethyl) aryl compound, in the presence of a base, such as 15 mM ammonium bicarbonate solution.
- a base such as 15 mM ammonium bicarbonate solution.
- Isotopic or radioactive labeled acetones are commercially available from various vendors. If there is a need for custom preparation of isotopic or radioactive labeled acetones, methods can be found in known arts, for example Rolf Voges, et al., Preparation of Compounds Labeled with Tritium and Carbon-14 (John Wiley & Sons (2009).
- Paclitaxel Activation Preparation of 2'-maleimide-paclitaxel: Dissolving one gram of paclitaxel (1.2 mmoles) in 160 mL of DCM, adding 0.12 mmole of DMAP and cooling the reaction mixture to 0 °C. To the cooled reaction mixture, was added 2.4 mmoles of 3- maleimidopropionic acid, and followed by 1.2 mmoles of DIC under stirring. The reaction mixture was then slowly warmed up to room temperature and the coupling reaction was allowed to proceed at room temperature for 18 h under continuous stirring.
- Strong anion exchange resin (chloride form, substitution 3 mmole/g, water content 50%, using 2 grams of resin per gram of peptide) was first washed three times with milli Q water, then three times with 1 N NaOH solution three times, 5 min/time, and then five times with milli Q water, 5 min/time. The resin was further washed with 75% ethanol water until the pH reaches about 7.4. This resin was treated with 10% acetic acid solution three times, five minutes each time. The resin was then washed with 1% acetic acid solution three times, five minutes each time. The resin was ready for the salt conversion of the purified peptide.
- the purified, lyophilized peptide was dissolved in 1% acetic acid solution and added to the prepared resin described above. The mixture was agitated or magnetically stirred at room temperature for 1 h. The supernatant was separated. The resin was washed three times with 1%) acetic acid solution. The supernatant and the washing solution were combined, filtered through a 0.22mm membrane and lyophilized, to afford a peptide in acetate salt.
- Peptide chain assembly The peptide chain of Cys(Mmt)-Tyr(tBu)-Lys(iPr,Boc)-
- N-terminal acetylation was carried out with 5 mL of a mixture of acetic anhydride/DIEA/DMF (1 : 1 :4, v/v/v) for 30 min at room temperature. The resin was then washed with DMF three time and then with DCM twice, dried under vacuum.
- H 4 HCO 3 was used to adjust the reaction mixture to pH 7.5.
- the conjugation reaction was completed in about half an hour as confirmed by MS.
- the final product was purified using a reverse-phased preparative column Daisogel (50x250mm, 8mm); mobile phases - Solvent A: 0.1%) TFA water; Solvent B: 0.1%> TFA acetonitrile. Fractions containing the target product were combined and lyophilized (a TFA salt).
- Peptide chain assembly The peptide chain of Cys(Trt)-Cys(Mmt)-Tyr(tBu)-
- Lys(iPr,Boc)-(D-Arg(Pbf))-2Nal-Gly-Cys(Mmt)-Lys(iPr,Boc)-Gly was assembled by standard Fmoc chemistry using Rink AM resin. Briefly, 3.6 g of Rink AM resin was swollen in DCM for 14 h and then washed four times with DMF. Removal of Fmoc was carried out in 20% piperidine in DMF for 20 min at room temperature and washed several times with DMF. Ninhydrin test was negative. Stepwise chain assembly started with Fmoc-Gly-OH from the C-terminal end of the linear peptide.
- Fmoc protection was removed again using 20% piperidine in DMF for 20 min.
- N-terminal acetylation was carried out with 20 mL of a mixture of acetic anhydride/DIEA/DMF (1 : 1 :4, v/v/v) for 30 min at room temperature. The resin was then washed with DMF three time and then with DCM twice, dried under vacuum.
- Peptide chain assembly The peptide chain of Cys(Trt)-Cys(Mmt)-Tyr(tBu)-
- Lys(iPr,Boc)-(D-Arg(Pbf))-2Nal-Gly-Cys(Mmt)-Lys(iPr,Boc)-Gly was assembled by standard Fmoc chemistry using Rink AM resin. Briefly, 3.6 g of Rink AM resin was swollen in DCM for 14 h and then washed four times with DMF. Removal of Fmoc was carried out in 20% piperidine in DMF for 20 min at room temperature and washed several times with DMF. Ninhydrin test was negative. Stepwise chain assembly started with Fmoc-Gly-OH from the C-terminal end of the linear peptide.
- Fmoc protection was removed again using 20% piperidine in DMF for 20 min.
- N-terminal acetylation was carried out with 20 mL of a mixture of acetic anhydride/DIEA/DMF (1 : 1 :4, v/v/v) for 30 min at room temperature. The resin was then washed with DMF three time and then with DCM twice, dried under vacuum.
- H 4 HCO 3 was used to adjust the reaction mixture to pH 7.5.
- the conjugation reaction was completed in about half an hour as confirmed by MS.
- the final product was purified using a reverse-phased preparative column Daisogel (50x250mm, 8mm); mobile phases - Solvent A: 0.1% TFA water; Solvent B: 0.1% TFA acetonitrile. Fractions containing the target product were combined and lyophilized (a TFA salt).
- Peptide chain assembly The peptide chain of Cys(Trt)-(mini-PEG6)-Cys(Mmt)-
- Tyr(tBu)-Lys(iPr,Boc)-(D-Arg(Pbf))-2Nal-Gly-Cys(Mmt)-Lys(iPr,Boc)-Gly (SEQ ID NO: 10) was assembled by standard Fmoc chemistry using Rink AM resin. Briefly, 3.6 g of Rink AM resin was swollen in DCM for 14 h and then washed four times with DMF. Removal of Fmoc was carried out in 20% piperidine in DMF for 20 min at room temperature and washed several times with DMF. Ninhydrin test was negative. Stepwise chain assembly started with Fmoc-Gly- OH from the C-terminal end of the linear peptide.
- Fmoc protection was removed again using 20% piperidine in DMF for 20 min.
- N-terminal acetylation was carried out with 20 mL of a mixture of acetic anhydride/DIEA/DMF (1 : 1 :4, v/v/v) for 30 min at room temperature. The resin was then washed with DMF three time and then with DCM twice, dried under vacuum.
- H 4 HCO 3 was used to adjust the reaction mixture to pH 7.5.
- the conjugation reaction was completed in about half an hour as confirmed by MS.
- the final product was purified using a reverse-phased preparative column Daisogel (50x250mm, 8mm); mobile phases - Solvent A: 0.1%) TFA water; Solvent B: 0.1%> TFA acetonitrile. Fractions containing the target product were combined and lyophilized (a TFA salt).
- Peptide chain assembly The peptide chain of Phe-Tyr(tBu)-Lys(iPr,Boc)-(D-
- Arg(Pbf))-2Nal-Gly-(D-Glu(OAll)-Lys(iPr,Boc)-(mini-PEG6)-Cys(Trt)-Gly was assembled by standard Fmoc chemistry using Rink AM resin. Briefly, 1.0 g of Rink AM resin was swollen in DCM for 14 h and then washed four times with DMF. Removal of Fmoc was carried out in 20% piperidine in DMF for 20 min at room temperature and washed several times with DMF. Ninhydrin test was negative. Stepwise chain assembly started with Fmoc-Gly- OH from the C-terminal end of the linear peptide.
- the deprotected side chain carboxylic acid of D-Glu was then activated with PyBOP ((benzotriazol- l-yloxy)-tris(pyrrolidino)-phosphonium hexafluorophosphate)/DIEA and cyclized to the alpha amino group of Phe residue on resin.
- PyBOP (benzotriazol- l-yloxy)-tris(pyrrolidino)-phosphonium hexafluorophosphate)/DIEA
- the cyclization was completed within 2 h, as confirmed by MS after a test cleavage.
- H 4 HC0 was used to adjust the reaction mixture to pH 7.5.
- the conjugation reaction was completed in about half an hour as confirmed by MS.
- the final product was purified using a reverse-phased preparative column Daisogel (50x250mm, 8mm); mobile phases - Solvent A: 0.1%) TFA water; Solvent B : 0.1%> TFA acetonitrile. Fractions containing the target product were combined and lyophilized (a TFA salt).
- Peptide chain assembly The peptide chain of Cys(Mmt)-Tyr(tBu)-Lys(iPr,Boc)-
- Fmoc protection was removed again using 20% piperidine in DMF for 20 min.
- N-terminal acetylation was carried out with 5 mL of a mixture of acetic anhydride/DIEA/DMF (1 : 1 :4, v/v/v) for 30 min at room temperature. The resin was then washed with DMF three time and then with DCM twice, dried under vacuum.
- NH 4 HCO 3 was used to adjust the reaction mixture to pH 7.5.
- the conjugation reaction was completed in about half an hour as confirmed by MS.
- the final product was purified using a reverse-phased preparative column Daisogel (50x250mm, 8mm); mobile phases - Solvent A: 0.1% TFA water; Solvent B: 0.1% TFA acetonitrile. Fractions containing the target product were combined and lyophilized (a TFA salt).
- Isotopic or radioactive labeled acetones are commercially available from various vendors. If there is a need for custom preparation of isotopic or radioactive labeled acetones, methods can be found in known arts, for example Rolf Voges, et al., Preparation of Compounds Labeled with Tritium and Carbon-14 (John Wiley & Sons (2009).
Abstract
Description
Claims
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201762554354P | 2017-09-05 | 2017-09-05 | |
PCT/US2018/018530 WO2019050564A1 (en) | 2017-09-05 | 2018-02-17 | High affinity cxcr4 selective binding conjugate and method for using the same |
Publications (2)
Publication Number | Publication Date |
---|---|
EP3679053A1 true EP3679053A1 (en) | 2020-07-15 |
EP3679053A4 EP3679053A4 (en) | 2021-10-27 |
Family
ID=65635072
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP18852912.7A Pending EP3679053A4 (en) | 2017-09-05 | 2018-02-17 | High affinity cxcr4 selective binding conjugate and method for using the same |
Country Status (6)
Country | Link |
---|---|
EP (1) | EP3679053A4 (en) |
JP (1) | JP2020532496A (en) |
KR (2) | KR20200043970A (en) |
CN (1) | CN111183146A (en) |
CA (1) | CA3065086A1 (en) |
WO (1) | WO2019050564A1 (en) |
Families Citing this family (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US11123437B2 (en) | 2017-09-05 | 2021-09-21 | Mainline Biosciences, Inc. | Selective CXCR4 binding peptide conjugate and methods for making and using the same |
JP2021165234A (en) * | 2018-07-03 | 2021-10-14 | 富士フイルム富山化学株式会社 | Cxcr4-binding compound or salt thereof, or complex of the same with metal |
WO2020210919A1 (en) * | 2019-04-18 | 2020-10-22 | Provincial Health Services Authority | Novel radiolabelled cxcr4-targeting compounds for diagnosis and therapy |
EP4097120A4 (en) * | 2020-01-26 | 2024-05-01 | Mainline Biosciences Shanghai Co Ltd | Isotopically labelled selective cxcr4 binding peptide conjugate and methods for making and using the same |
CN114832113B (en) * | 2022-03-22 | 2023-06-20 | 重庆医科大学 | Hydrophobic drug-maleimide derivative and active drug-carrying liposome and application thereof |
WO2023201435A1 (en) * | 2022-04-20 | 2023-10-26 | Provincial Health Services Authority | Cxcr4-targeting compounds, and methods of making and using the same |
Family Cites Families (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR20090041360A (en) * | 2006-02-27 | 2009-04-28 | 테크니쉐 유니베르시테트 뮌헨 | Cancer imaging and treatment |
PE20090299A1 (en) * | 2007-05-30 | 2009-03-19 | Lilly Co Eli | CYCLIC PEPTIDE CXCR4 ANTAGONISTS |
IT1397901B1 (en) * | 2010-01-26 | 2013-02-04 | Consiglio Nazionale Ricerche | CYCLIC PEPTIDES THAT BIND THE CXCR4 RECEPTOR AND THEIR USE IN MEDICAL AND DIAGNOSTIC FIELDS. |
CN102626522B (en) * | 2012-04-12 | 2014-09-10 | 韩彦江 | Polypeptide radioactive diagnosis and treatment medicament based on chemotactic factor receptor CXCR4 polypeptide antagonist |
US9617308B2 (en) * | 2012-06-06 | 2017-04-11 | Polyphor Ag | Beta-hairpin peptidomimetics |
US9790286B2 (en) * | 2013-01-02 | 2017-10-17 | Lucia Irene Gonzalez | Stereoisomer peptides, their polymer conjugates, their encapsulation into nanoparticles, and uses thereof for the treatment of diseases caused by abnormal angiogenesis |
US10919938B2 (en) * | 2014-06-06 | 2021-02-16 | Technische Universität München | Modified cyclopentapeptides and uses thereof |
-
2018
- 2018-02-17 KR KR1020207000227A patent/KR20200043970A/en not_active IP Right Cessation
- 2018-02-17 CA CA3065086A patent/CA3065086A1/en active Pending
- 2018-02-17 EP EP18852912.7A patent/EP3679053A4/en active Pending
- 2018-02-17 WO PCT/US2018/018530 patent/WO2019050564A1/en unknown
- 2018-02-17 JP JP2020504380A patent/JP2020532496A/en active Pending
- 2018-02-17 KR KR1020237034343A patent/KR20230145543A/en active Search and Examination
- 2018-02-17 CN CN201880049498.7A patent/CN111183146A/en active Pending
Also Published As
Publication number | Publication date |
---|---|
KR20200043970A (en) | 2020-04-28 |
CN111183146A (en) | 2020-05-19 |
KR20230145543A (en) | 2023-10-17 |
CA3065086A1 (en) | 2019-03-14 |
JP2020532496A (en) | 2020-11-12 |
EP3679053A4 (en) | 2021-10-27 |
WO2019050564A1 (en) | 2019-03-14 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
WO2019050564A1 (en) | High affinity cxcr4 selective binding conjugate and method for using the same | |
KR101169846B1 (en) | Cyclic peptide cxcr4 antagonists | |
KR100668546B1 (en) | Peptides and Compounds That Bind to a Receptor | |
US10870681B2 (en) | CXCR4 antagonists and methods of use | |
US11883501B2 (en) | Selective CXCR4 binding peptide conjugate and methods for making and using the same | |
US10639379B2 (en) | High affinity CXCR4 selective binding conjugate and method for using the same | |
WO2021150258A1 (en) | Isotopically labelled selective cxcr4 binding peptide conjugate and methods for making and using the same | |
US20240082346A1 (en) | Composition Comprising an Antiviral Agent and a CXCR4 Selective Antagonist and Methods For Using the Same |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE INTERNATIONAL PUBLICATION HAS BEEN MADE |
|
PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: REQUEST FOR EXAMINATION WAS MADE |
|
17P | Request for examination filed |
Effective date: 20191126 |
|
AK | Designated contracting states |
Kind code of ref document: A1 Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR |
|
AX | Request for extension of the european patent |
Extension state: BA ME |
|
DAV | Request for validation of the european patent (deleted) | ||
DAX | Request for extension of the european patent (deleted) | ||
RIC1 | Information provided on ipc code assigned before grant |
Ipc: C07K 7/06 20060101AFI20210621BHEP Ipc: C07K 7/50 20060101ALI20210621BHEP Ipc: C07K 5/12 20060101ALI20210621BHEP Ipc: A61K 38/00 20060101ALI20210621BHEP Ipc: A61K 49/00 20060101ALI20210621BHEP Ipc: C07K 14/705 20060101ALI20210621BHEP |
|
A4 | Supplementary search report drawn up and despatched |
Effective date: 20210927 |
|
RIC1 | Information provided on ipc code assigned before grant |
Ipc: C07K 14/705 20060101ALI20210921BHEP Ipc: A61K 49/00 20060101ALI20210921BHEP Ipc: A61K 38/00 20060101ALI20210921BHEP Ipc: C07K 5/12 20060101ALI20210921BHEP Ipc: C07K 7/50 20060101ALI20210921BHEP Ipc: C07K 7/06 20060101AFI20210921BHEP |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: EXAMINATION IS IN PROGRESS |
|
17Q | First examination report despatched |
Effective date: 20240314 |