CN114642740A - 一种靶向trop2的抗体药物偶联物、其制备方法及应用 - Google Patents
一种靶向trop2的抗体药物偶联物、其制备方法及应用 Download PDFInfo
- Publication number
- CN114642740A CN114642740A CN202011514030.6A CN202011514030A CN114642740A CN 114642740 A CN114642740 A CN 114642740A CN 202011514030 A CN202011514030 A CN 202011514030A CN 114642740 A CN114642740 A CN 114642740A
- Authority
- CN
- China
- Prior art keywords
- alkyl
- substituted
- independently
- group
- butyl
- 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
- 229940049595 antibody-drug conjugate Drugs 0.000 title claims abstract description 55
- 239000000611 antibody drug conjugate Substances 0.000 title claims abstract description 45
- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- 101150117918 Tacstd2 gene Proteins 0.000 claims abstract description 34
- 102100027212 Tumor-associated calcium signal transducer 2 Human genes 0.000 claims abstract description 34
- 239000003814 drug Substances 0.000 claims abstract description 31
- 125000000217 alkyl group Chemical group 0.000 claims description 72
- 150000001875 compounds Chemical class 0.000 claims description 40
- 206010028980 Neoplasm Diseases 0.000 claims description 33
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 32
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 27
- 238000000034 method Methods 0.000 claims description 25
- 229910052736 halogen Inorganic materials 0.000 claims description 23
- 150000002367 halogens Chemical class 0.000 claims description 23
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 19
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 19
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 19
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 19
- 150000003839 salts Chemical class 0.000 claims description 19
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 19
- 125000003295 alanine group Chemical group N[C@@H](C)C(=O)* 0.000 claims description 16
- 125000002987 valine group Chemical group [H]N([H])C([H])(C(*)=O)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 16
- 239000000126 substance Substances 0.000 claims description 14
- 238000005859 coupling reaction Methods 0.000 claims description 12
- 241000282414 Homo sapiens Species 0.000 claims description 10
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 9
- 229910052731 fluorine Inorganic materials 0.000 claims description 9
- 239000011737 fluorine Substances 0.000 claims description 9
- 206010017758 gastric cancer Diseases 0.000 claims description 9
- 239000008194 pharmaceutical composition Substances 0.000 claims description 8
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 8
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 7
- 125000003630 glycyl group Chemical group [H]N([H])C([H])([H])C(*)=O 0.000 claims description 7
- COLNVLDHVKWLRT-QMMMGPOBSA-N phenylalanine group Chemical group N[C@@H](CC1=CC=CC=C1)C(=O)O COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 claims description 7
- 201000011549 stomach cancer Diseases 0.000 claims description 7
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 6
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 6
- 201000002528 pancreatic cancer Diseases 0.000 claims description 6
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 6
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 5
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 5
- 208000003721 Triple Negative Breast Neoplasms Diseases 0.000 claims description 5
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 5
- 229910052794 bromium Inorganic materials 0.000 claims description 5
- 229910052801 chlorine Inorganic materials 0.000 claims description 5
- 239000000460 chlorine Substances 0.000 claims description 5
- 208000022679 triple-negative breast carcinoma Diseases 0.000 claims description 5
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 4
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 239000011630 iodine Substances 0.000 claims description 3
- 229910052740 iodine Inorganic materials 0.000 claims description 3
- 125000000741 isoleucyl group Chemical group [H]N([H])C(C(C([H])([H])[H])C([H])([H])C([H])([H])[H])C(=O)O* 0.000 claims description 3
- 125000001909 leucine group Chemical group [H]N(*)C(C(*)=O)C([H])([H])C(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- 229940124531 pharmaceutical excipient Drugs 0.000 claims description 3
- 125000001500 prolyl group Chemical group [H]N1C([H])(C(=O)[*])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 3
- 125000003396 thiol group Chemical group [H]S* 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 230000002265 prevention Effects 0.000 claims description 2
- 229940121649 protein inhibitor Drugs 0.000 claims description 2
- 239000012268 protein inhibitor Substances 0.000 claims description 2
- 150000003568 thioethers Chemical group 0.000 claims description 2
- 125000003275 alpha amino acid group Chemical group 0.000 claims 2
- 210000004027 cell Anatomy 0.000 abstract description 35
- 229940079593 drug Drugs 0.000 abstract description 28
- 230000000694 effects Effects 0.000 abstract description 14
- 230000008685 targeting Effects 0.000 abstract description 6
- 230000002401 inhibitory effect Effects 0.000 abstract description 5
- 210000004881 tumor cell Anatomy 0.000 abstract description 5
- 230000005764 inhibitory process Effects 0.000 abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 75
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 60
- 239000000543 intermediate Substances 0.000 description 53
- 238000006243 chemical reaction Methods 0.000 description 36
- 238000003786 synthesis reaction Methods 0.000 description 30
- 230000015572 biosynthetic process Effects 0.000 description 29
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 24
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 23
- 230000002829 reductive effect Effects 0.000 description 23
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 21
- 239000012043 crude product Substances 0.000 description 21
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 17
- 239000002904 solvent Substances 0.000 description 17
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 15
- -1 saturated cyclic hydrocarbon radical Chemical group 0.000 description 14
- 238000010898 silica gel chromatography Methods 0.000 description 14
- 239000000243 solution Substances 0.000 description 14
- 201000011510 cancer Diseases 0.000 description 13
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 9
- 238000004821 distillation Methods 0.000 description 9
- 238000000338 in vitro Methods 0.000 description 9
- 230000002147 killing effect Effects 0.000 description 9
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 8
- 239000012074 organic phase Substances 0.000 description 8
- 239000000523 sample Substances 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- 238000005160 1H NMR spectroscopy Methods 0.000 description 7
- 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 description 7
- 239000002253 acid Substances 0.000 description 7
- 150000001413 amino acids Chemical group 0.000 description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 6
- 239000000872 buffer Substances 0.000 description 6
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 6
- 239000000562 conjugate Substances 0.000 description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 6
- 125000005647 linker group Chemical group 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- 102000004225 Cathepsin B Human genes 0.000 description 5
- 108090000712 Cathepsin B Proteins 0.000 description 5
- 125000004432 carbon atom Chemical group C* 0.000 description 5
- 230000008878 coupling Effects 0.000 description 5
- 238000010168 coupling process Methods 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 238000000746 purification Methods 0.000 description 5
- 150000003384 small molecules Chemical class 0.000 description 5
- 239000007858 starting material Substances 0.000 description 5
- 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 4
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 4
- 241000880493 Leptailurus serval Species 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 229940127089 cytotoxic agent Drugs 0.000 description 4
- 239000002254 cytotoxic agent Substances 0.000 description 4
- 230000001472 cytotoxic effect Effects 0.000 description 4
- 238000011161 development Methods 0.000 description 4
- 230000029087 digestion Effects 0.000 description 4
- 238000001976 enzyme digestion Methods 0.000 description 4
- ZVYVPGLRVWUPMP-FYSMJZIKSA-N exatecan Chemical compound C1C[C@H](N)C2=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC3=CC(F)=C(C)C1=C32 ZVYVPGLRVWUPMP-FYSMJZIKSA-N 0.000 description 4
- 229950009429 exatecan Drugs 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 239000012046 mixed solvent Substances 0.000 description 4
- 230000007935 neutral effect Effects 0.000 description 4
- 108090000623 proteins and genes Proteins 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- GKQLYSROISKDLL-UHFFFAOYSA-N EEDQ Chemical compound C1=CC=C2N(C(=O)OCC)C(OCC)C=CC2=C1 GKQLYSROISKDLL-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- SITLTJHOQZFJGG-UHFFFAOYSA-N N-L-alpha-glutamyl-L-valine Natural products CC(C)C(C(O)=O)NC(=O)C(N)CCC(O)=O SITLTJHOQZFJGG-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 229930040373 Paraformaldehyde Natural products 0.000 description 3
- IHCXPSYCHXFXKT-DCAQKATOSA-N Pro-Arg-Glu Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(O)=O IHCXPSYCHXFXKT-DCAQKATOSA-N 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 230000009471 action Effects 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- 239000012964 benzotriazole Substances 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 238000012258 culturing Methods 0.000 description 3
- 125000000753 cycloalkyl group Chemical group 0.000 description 3
- 231100000433 cytotoxic Toxicity 0.000 description 3
- 230000012202 endocytosis Effects 0.000 description 3
- 239000013613 expression plasmid Substances 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 239000012091 fetal bovine serum Substances 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 125000000524 functional group Chemical group 0.000 description 3
- 238000002868 homogeneous time resolved fluorescence Methods 0.000 description 3
- NQMRYBIKMRVZLB-UHFFFAOYSA-N methylamine hydrochloride Chemical compound [Cl-].[NH3+]C NQMRYBIKMRVZLB-UHFFFAOYSA-N 0.000 description 3
- 229920002866 paraformaldehyde Polymers 0.000 description 3
- 239000000902 placebo Substances 0.000 description 3
- 229940068196 placebo Drugs 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 3
- 235000018102 proteins Nutrition 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 238000010791 quenching Methods 0.000 description 3
- 150000003254 radicals Chemical class 0.000 description 3
- WINGEFIITRDOLJ-UHFFFAOYSA-N tert-butyl 2-hydroxyacetate Chemical compound CC(C)(C)OC(=O)CO WINGEFIITRDOLJ-UHFFFAOYSA-N 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 3
- 108010044292 tryptophyltyrosine Proteins 0.000 description 3
- GHOKWGTUZJEAQD-ZETCQYMHSA-N (D)-(+)-Pantothenic acid Chemical compound OCC(C)(C)[C@@H](O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-ZETCQYMHSA-N 0.000 description 2
- WXTMDXOMEHJXQO-UHFFFAOYSA-N 2,5-dihydroxybenzoic acid Chemical compound OC(=O)C1=CC(O)=CC=C1O WXTMDXOMEHJXQO-UHFFFAOYSA-N 0.000 description 2
- XHIMBQWQWUOCEY-UHFFFAOYSA-N 2-[tert-butyl(dimethyl)silyl]oxyacetic acid Chemical compound CC(C)(C)[Si](C)(C)OCC(O)=O XHIMBQWQWUOCEY-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 2
- 206010006187 Breast cancer Diseases 0.000 description 2
- 208000026310 Breast neoplasm Diseases 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical group [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- 238000002965 ELISA Methods 0.000 description 2
- 239000007821 HATU Substances 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- TYYLDKGBCJGJGW-UHFFFAOYSA-N L-tryptophan-L-tyrosine Natural products C=1NC2=CC=CC=C2C=1CC(N)C(=O)NC(C(O)=O)CC1=CC=C(O)C=C1 TYYLDKGBCJGJGW-UHFFFAOYSA-N 0.000 description 2
- MPGHETGWWWUHPY-CIUDSAMLSA-N Lys-Ala-Asp Chemical compound OC(=O)C[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CCCCN MPGHETGWWWUHPY-CIUDSAMLSA-N 0.000 description 2
- PDIDTSZKKFEDMB-UWVGGRQHSA-N Lys-Pro-Gly Chemical compound [H]N[C@@H](CCCCN)C(=O)N1CCC[C@H]1C(=O)NCC(O)=O PDIDTSZKKFEDMB-UWVGGRQHSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 108010079364 N-glycylalanine Proteins 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- CGBYDGAJHSOGFQ-LPEHRKFASA-N Pro-Ala-Pro Chemical compound C[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@@H]2CCCN2 CGBYDGAJHSOGFQ-LPEHRKFASA-N 0.000 description 2
- FDMKYQQYJKYCLV-GUBZILKMSA-N Pro-Pro-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@H]1NCCC1 FDMKYQQYJKYCLV-GUBZILKMSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 108020004511 Recombinant DNA Proteins 0.000 description 2
- UIGMAMGZOJVTDN-WHFBIAKZSA-N Ser-Gly-Ser Chemical compound OC[C@H](N)C(=O)NCC(=O)N[C@@H](CO)C(O)=O UIGMAMGZOJVTDN-WHFBIAKZSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 230000000259 anti-tumor effect Effects 0.000 description 2
- 239000000427 antigen Substances 0.000 description 2
- 102000036639 antigens Human genes 0.000 description 2
- 108091007433 antigens Proteins 0.000 description 2
- 108010052670 arginyl-glutamyl-glutamic acid Proteins 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 235000014633 carbohydrates Nutrition 0.000 description 2
- 150000001720 carbohydrates Chemical class 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 210000004978 chinese hamster ovary cell Anatomy 0.000 description 2
- 229960004106 citric acid Drugs 0.000 description 2
- 230000021615 conjugation Effects 0.000 description 2
- 125000000151 cysteine group Chemical group N[C@@H](CS)C(=O)* 0.000 description 2
- 108010060199 cysteinylproline Proteins 0.000 description 2
- 238000011033 desalting Methods 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 239000001530 fumaric acid Substances 0.000 description 2
- 208000010749 gastric carcinoma Diseases 0.000 description 2
- VPZXBVLAVMBEQI-UHFFFAOYSA-N glycyl-DL-alpha-alanine Natural products OC(=O)C(C)NC(=O)CN VPZXBVLAVMBEQI-UHFFFAOYSA-N 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 229940127121 immunoconjugate Drugs 0.000 description 2
- 230000005917 in vivo anti-tumor Effects 0.000 description 2
- 239000012442 inert solvent Substances 0.000 description 2
- 230000003834 intracellular effect Effects 0.000 description 2
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 2
- KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical compound CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 description 2
- TWBYWOBDOCUKOW-UHFFFAOYSA-N isonicotinic acid Chemical compound OC(=O)C1=CC=NC=C1 TWBYWOBDOCUKOW-UHFFFAOYSA-N 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 2
- 108010017391 lysylvaline Proteins 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- WLJNZVDCPSBLRP-UHFFFAOYSA-N pamoic acid Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 WLJNZVDCPSBLRP-UHFFFAOYSA-N 0.000 description 2
- XNGIFLGASWRNHJ-UHFFFAOYSA-N phthalic acid Chemical compound OC(=O)C1=CC=CC=C1C(O)=O XNGIFLGASWRNHJ-UHFFFAOYSA-N 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000004393 prognosis Methods 0.000 description 2
- 108010031719 prolyl-serine Proteins 0.000 description 2
- 108010090894 prolylleucine Proteins 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 230000000171 quenching effect Effects 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 238000005070 sampling Methods 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 201000000498 stomach carcinoma Diseases 0.000 description 2
- TYFQFVWCELRYAO-UHFFFAOYSA-N suberic acid Chemical compound OC(=O)CCCCCCC(O)=O TYFQFVWCELRYAO-UHFFFAOYSA-N 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- RXJKFRMDXUJTEX-UHFFFAOYSA-N triethylphosphine Chemical compound CCP(CC)CC RXJKFRMDXUJTEX-UHFFFAOYSA-N 0.000 description 2
- 239000005051 trimethylchlorosilane Substances 0.000 description 2
- 239000004474 valine Substances 0.000 description 2
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- XVNBLPHVIQXLMS-REOHCLBHSA-N (2s)-2-azidopropanoic acid Chemical compound OC(=O)[C@H](C)N=[N+]=[N-] XVNBLPHVIQXLMS-REOHCLBHSA-N 0.000 description 1
- AXKGIPZJYUNAIW-UHFFFAOYSA-N (4-aminophenyl)methanol Chemical compound NC1=CC=C(CO)C=C1 AXKGIPZJYUNAIW-UHFFFAOYSA-N 0.000 description 1
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 1
- NAOLWIGVYRIGTP-UHFFFAOYSA-N 1,3,5-trihydroxyanthracene-9,10-dione Chemical compound C1=CC(O)=C2C(=O)C3=CC(O)=CC(O)=C3C(=O)C2=C1 NAOLWIGVYRIGTP-UHFFFAOYSA-N 0.000 description 1
- TUSDEZXZIZRFGC-UHFFFAOYSA-N 1-O-galloyl-3,6-(R)-HHDP-beta-D-glucose Natural products OC1C(O2)COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC1C(O)C2OC(=O)C1=CC(O)=C(O)C(O)=C1 TUSDEZXZIZRFGC-UHFFFAOYSA-N 0.000 description 1
- VSTXCZGEEVFJES-UHFFFAOYSA-N 1-cycloundecyl-1,5-diazacycloundec-5-ene Chemical compound C1CCCCCC(CCCC1)N1CCCCCC=NCCC1 VSTXCZGEEVFJES-UHFFFAOYSA-N 0.000 description 1
- 101150028074 2 gene Proteins 0.000 description 1
- 150000003923 2,5-pyrrolediones Chemical class 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
- YLZOPXRUQYQQID-UHFFFAOYSA-N 3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)-1-[4-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]piperazin-1-yl]propan-1-one Chemical compound N1N=NC=2CN(CCC=21)CCC(=O)N1CCN(CC1)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F YLZOPXRUQYQQID-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- MNHMVGLVJFKQEN-UHFFFAOYSA-N 3-phosphanylpropanoic acid;hydrochloride Chemical compound Cl.OC(=O)CCP.OC(=O)CCP.OC(=O)CCP MNHMVGLVJFKQEN-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- JBGSZRYCXBPWGX-BQBZGAKWSA-N Ala-Arg-Gly Chemical compound OC(=O)CNC(=O)[C@@H](NC(=O)[C@@H](N)C)CCCN=C(N)N JBGSZRYCXBPWGX-BQBZGAKWSA-N 0.000 description 1
- WCBVQNZTOKJWJS-ACZMJKKPSA-N Ala-Cys-Glu Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(O)=O)C(O)=O WCBVQNZTOKJWJS-ACZMJKKPSA-N 0.000 description 1
- OBVSBEYOMDWLRJ-BFHQHQDPSA-N Ala-Gly-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)CNC(=O)[C@H](C)N OBVSBEYOMDWLRJ-BFHQHQDPSA-N 0.000 description 1
- MNZHHDPWDWQJCQ-YUMQZZPRSA-N Ala-Leu-Gly Chemical compound C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)NCC(O)=O MNZHHDPWDWQJCQ-YUMQZZPRSA-N 0.000 description 1
- SUHLZMHFRALVSY-YUMQZZPRSA-N Ala-Lys-Gly Chemical compound NCCCC[C@H](NC(=O)[C@@H](N)C)C(=O)NCC(O)=O SUHLZMHFRALVSY-YUMQZZPRSA-N 0.000 description 1
- WQKAQKZRDIZYNV-VZFHVOOUSA-N Ala-Ser-Thr Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(O)=O WQKAQKZRDIZYNV-VZFHVOOUSA-N 0.000 description 1
- ARHJJAAWNWOACN-FXQIFTODSA-N Ala-Ser-Val Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O ARHJJAAWNWOACN-FXQIFTODSA-N 0.000 description 1
- YJHKTAMKPGFJCT-NRPADANISA-N Ala-Val-Glu Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O YJHKTAMKPGFJCT-NRPADANISA-N 0.000 description 1
- ZDILXFDENZVOTL-BPNCWPANSA-N Ala-Val-Tyr Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O ZDILXFDENZVOTL-BPNCWPANSA-N 0.000 description 1
- PNQWAUXQDBIJDY-GUBZILKMSA-N Arg-Glu-Glu Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O PNQWAUXQDBIJDY-GUBZILKMSA-N 0.000 description 1
- AOHKLEBWKMKITA-IHRRRGAJSA-N Arg-Phe-Ser Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CO)C(=O)O)NC(=O)[C@H](CCCN=C(N)N)N AOHKLEBWKMKITA-IHRRRGAJSA-N 0.000 description 1
- ZUVMUOOHJYNJPP-XIRDDKMYSA-N Arg-Trp-Gln Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](CCC(N)=O)C(O)=O ZUVMUOOHJYNJPP-XIRDDKMYSA-N 0.000 description 1
- ULBHWNVWSCJLCO-NHCYSSNCSA-N Arg-Val-Glu Chemical compound OC(=O)CC[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](N)CCCN=C(N)N ULBHWNVWSCJLCO-NHCYSSNCSA-N 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- SRUUBQBAVNQZGJ-LAEOZQHASA-N Asn-Gln-Val Chemical compound CC(C)[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CC(=O)N)N SRUUBQBAVNQZGJ-LAEOZQHASA-N 0.000 description 1
- WONGRTVAMHFGBE-WDSKDSINSA-N Asn-Gly-Gln Chemical compound C(CC(=O)N)[C@@H](C(=O)O)NC(=O)CNC(=O)[C@H](CC(=O)N)N WONGRTVAMHFGBE-WDSKDSINSA-N 0.000 description 1
- RBOBTTLFPRSXKZ-BZSNNMDCSA-N Asn-Phe-Tyr Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O RBOBTTLFPRSXKZ-BZSNNMDCSA-N 0.000 description 1
- HNXWVVHIGTZTBO-LKXGYXEUSA-N Asn-Ser-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O HNXWVVHIGTZTBO-LKXGYXEUSA-N 0.000 description 1
- PUUPMDXIHCOPJU-HJGDQZAQSA-N Asn-Thr-Lys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CC(=O)N)N)O PUUPMDXIHCOPJU-HJGDQZAQSA-N 0.000 description 1
- KZYSHAMXEBPJBD-JRQIVUDYSA-N Asn-Thr-Tyr Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O KZYSHAMXEBPJBD-JRQIVUDYSA-N 0.000 description 1
- QNNBHTFDFFFHGC-KKUMJFAQSA-N Asn-Tyr-Lys Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CC(=O)N)N)O QNNBHTFDFFFHGC-KKUMJFAQSA-N 0.000 description 1
- MJIJBEYEHBKTIM-BYULHYEWSA-N Asn-Val-Asn Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](CC(=O)N)N MJIJBEYEHBKTIM-BYULHYEWSA-N 0.000 description 1
- XYBJLTKSGFBLCS-QXEWZRGKSA-N Asp-Arg-Val Chemical compound NC(N)=NCCC[C@@H](C(=O)N[C@@H](C(C)C)C(O)=O)NC(=O)[C@@H](N)CC(O)=O XYBJLTKSGFBLCS-QXEWZRGKSA-N 0.000 description 1
- YNQIDCRRTWGHJD-ZLUOBGJFSA-N Asp-Asn-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](N)CC(O)=O YNQIDCRRTWGHJD-ZLUOBGJFSA-N 0.000 description 1
- HSWYMWGDMPLTTH-FXQIFTODSA-N Asp-Glu-Gln Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(O)=O HSWYMWGDMPLTTH-FXQIFTODSA-N 0.000 description 1
- SNDBKTFJWVEVPO-WHFBIAKZSA-N Asp-Gly-Ser Chemical compound [H]N[C@@H](CC(O)=O)C(=O)NCC(=O)N[C@@H](CO)C(O)=O SNDBKTFJWVEVPO-WHFBIAKZSA-N 0.000 description 1
- QNFRBNZGVVKBNJ-PEFMBERDSA-N Asp-Ile-Gln Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](CC(=O)O)N QNFRBNZGVVKBNJ-PEFMBERDSA-N 0.000 description 1
- DPNWSMBUYCLEDG-CIUDSAMLSA-N Asp-Lys-Ser Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(O)=O DPNWSMBUYCLEDG-CIUDSAMLSA-N 0.000 description 1
- DONWIPDSZZJHHK-HJGDQZAQSA-N Asp-Lys-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC(=O)O)N)O DONWIPDSZZJHHK-HJGDQZAQSA-N 0.000 description 1
- VNXQRBXEQXLERQ-CIUDSAMLSA-N Asp-Ser-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(=O)O)N VNXQRBXEQXLERQ-CIUDSAMLSA-N 0.000 description 1
- YIDFBWRHIYOYAA-LKXGYXEUSA-N Asp-Ser-Thr Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(O)=O YIDFBWRHIYOYAA-LKXGYXEUSA-N 0.000 description 1
- MNQMTYSEKZHIDF-GCJQMDKQSA-N Asp-Thr-Ala Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C)C(O)=O MNQMTYSEKZHIDF-GCJQMDKQSA-N 0.000 description 1
- JSNWZMFSLIWAHS-HJGDQZAQSA-N Asp-Thr-Leu Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)O)NC(=O)[C@H](CC(=O)O)N)O JSNWZMFSLIWAHS-HJGDQZAQSA-N 0.000 description 1
- 238000011729 BALB/c nude mouse Methods 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 206010008342 Cervix carcinoma Diseases 0.000 description 1
- GHOKWGTUZJEAQD-UHFFFAOYSA-N Chick antidermatitis factor Natural products OCC(C)(C)C(O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-UHFFFAOYSA-N 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 1
- OHLLDUNVMPPUMD-DCAQKATOSA-N Cys-Leu-Val Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](C(C)C)C(=O)O)NC(=O)[C@H](CS)N OHLLDUNVMPPUMD-DCAQKATOSA-N 0.000 description 1
- OZHXXYOHPLLLMI-CIUDSAMLSA-N Cys-Lys-Ala Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(O)=O OZHXXYOHPLLLMI-CIUDSAMLSA-N 0.000 description 1
- NDNZRWUDUMTITL-FXQIFTODSA-N Cys-Ser-Val Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O NDNZRWUDUMTITL-FXQIFTODSA-N 0.000 description 1
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 description 1
- 239000001263 FEMA 3042 Substances 0.000 description 1
- OYTPNWYZORARHL-XHNCKOQMSA-N Gln-Ala-Pro Chemical compound C[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CCC(=O)N)N OYTPNWYZORARHL-XHNCKOQMSA-N 0.000 description 1
- DHNWZLGBTPUTQQ-QEJZJMRPSA-N Gln-Asp-Trp Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](CCC(=O)N)N DHNWZLGBTPUTQQ-QEJZJMRPSA-N 0.000 description 1
- XKBASPWPBXNVLQ-WDSKDSINSA-N Gln-Gly-Asn Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)NCC(=O)N[C@@H](CC(N)=O)C(O)=O XKBASPWPBXNVLQ-WDSKDSINSA-N 0.000 description 1
- FGYPOQPQTUNESW-IUCAKERBSA-N Gln-Gly-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)CNC(=O)[C@H](CCC(=O)N)N FGYPOQPQTUNESW-IUCAKERBSA-N 0.000 description 1
- SMLDOQHTOAAFJQ-WDSKDSINSA-N Gln-Gly-Ser Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)NCC(=O)N[C@@H](CO)C(O)=O SMLDOQHTOAAFJQ-WDSKDSINSA-N 0.000 description 1
- OOLCSQQPSLIETN-JYJNAYRXSA-N Gln-His-Tyr Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)O)NC(=O)[C@H](CC2=CN=CN2)NC(=O)[C@H](CCC(=O)N)N)O OOLCSQQPSLIETN-JYJNAYRXSA-N 0.000 description 1
- ZEEPYMXTJWIMSN-GUBZILKMSA-N Gln-Lys-Ser Chemical compound NCCCC[C@@H](C(=O)N[C@@H](CO)C(O)=O)NC(=O)[C@@H](N)CCC(N)=O ZEEPYMXTJWIMSN-GUBZILKMSA-N 0.000 description 1
- ZFBBMCKQSNJZSN-AUTRQRHGSA-N Gln-Val-Gln Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O ZFBBMCKQSNJZSN-AUTRQRHGSA-N 0.000 description 1
- PAQUJCSYVIBPLC-AVGNSLFASA-N Glu-Asp-Phe Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 PAQUJCSYVIBPLC-AVGNSLFASA-N 0.000 description 1
- CKOFNWCLWRYUHK-XHNCKOQMSA-N Glu-Asp-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC(=O)O)NC(=O)[C@H](CCC(=O)O)N)C(=O)O CKOFNWCLWRYUHK-XHNCKOQMSA-N 0.000 description 1
- HUFCEIHAFNVSNR-IHRRRGAJSA-N Glu-Gln-Tyr Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 HUFCEIHAFNVSNR-IHRRRGAJSA-N 0.000 description 1
- MWMJCGBSIORNCD-AVGNSLFASA-N Glu-Leu-Leu Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O MWMJCGBSIORNCD-AVGNSLFASA-N 0.000 description 1
- IVGJYOOGJLFKQE-AVGNSLFASA-N Glu-Leu-Lys Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CCC(=O)O)N IVGJYOOGJLFKQE-AVGNSLFASA-N 0.000 description 1
- QDMVXRNLOPTPIE-WDCWCFNPSA-N Glu-Lys-Thr Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(O)=O QDMVXRNLOPTPIE-WDCWCFNPSA-N 0.000 description 1
- DMYACXMQUABZIQ-NRPADANISA-N Glu-Ser-Val Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O DMYACXMQUABZIQ-NRPADANISA-N 0.000 description 1
- ZYRXTRTUCAVNBQ-GVXVVHGQSA-N Glu-Val-Lys Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CCC(=O)O)N ZYRXTRTUCAVNBQ-GVXVVHGQSA-N 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- XCLCVBYNGXEVDU-WHFBIAKZSA-N Gly-Asn-Ser Chemical compound NCC(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(O)=O XCLCVBYNGXEVDU-WHFBIAKZSA-N 0.000 description 1
- BYYNJRSNDARRBX-YFKPBYRVSA-N Gly-Gln-Gly Chemical compound NCC(=O)N[C@@H](CCC(N)=O)C(=O)NCC(O)=O BYYNJRSNDARRBX-YFKPBYRVSA-N 0.000 description 1
- BIRKKBCSAIHDDF-WDSKDSINSA-N Gly-Glu-Cys Chemical compound NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CS)C(O)=O BIRKKBCSAIHDDF-WDSKDSINSA-N 0.000 description 1
- UQJNXZSSGQIPIQ-FBCQKBJTSA-N Gly-Gly-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)CNC(=O)CN UQJNXZSSGQIPIQ-FBCQKBJTSA-N 0.000 description 1
- ICUTTWWCDIIIEE-BQBZGAKWSA-N Gly-Met-Asn Chemical compound CSCC[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)CN ICUTTWWCDIIIEE-BQBZGAKWSA-N 0.000 description 1
- HAOUOFNNJJLVNS-BQBZGAKWSA-N Gly-Pro-Ser Chemical compound NCC(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O HAOUOFNNJJLVNS-BQBZGAKWSA-N 0.000 description 1
- NVTPVQLIZCOJFK-FOHZUACHSA-N Gly-Thr-Asp Chemical compound [H]NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(O)=O)C(O)=O NVTPVQLIZCOJFK-FOHZUACHSA-N 0.000 description 1
- WTUSRDZLLWGYAT-KCTSRDHCSA-N Gly-Trp-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CC1=CNC2=CC=CC=C21)NC(=O)CN WTUSRDZLLWGYAT-KCTSRDHCSA-N 0.000 description 1
- GBYYQVBXFVDJPJ-WLTAIBSBSA-N Gly-Tyr-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)NC(=O)CN)O GBYYQVBXFVDJPJ-WLTAIBSBSA-N 0.000 description 1
- SYOJVRNQCXYEOV-XVKPBYJWSA-N Gly-Val-Glu Chemical compound [H]NCC(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O SYOJVRNQCXYEOV-XVKPBYJWSA-N 0.000 description 1
- FULZDMOZUZKGQU-ONGXEEELSA-N Gly-Val-His Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)NC(=O)CN FULZDMOZUZKGQU-ONGXEEELSA-N 0.000 description 1
- MAABHGXCIBEYQR-XVYDVKMFSA-N His-Asn-Ala Chemical compound C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](CC1=CN=CN1)N MAABHGXCIBEYQR-XVYDVKMFSA-N 0.000 description 1
- HIAHVKLTHNOENC-HGNGGELXSA-N His-Glu-Ala Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(O)=O HIAHVKLTHNOENC-HGNGGELXSA-N 0.000 description 1
- TVMNTHXFRSXZGR-IHRRRGAJSA-N His-Lys-Val Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(O)=O TVMNTHXFRSXZGR-IHRRRGAJSA-N 0.000 description 1
- HZWWOGWOBQBETJ-CUJWVEQBSA-N His-Thr-Cys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CC1=CN=CN1)N)O HZWWOGWOBQBETJ-CUJWVEQBSA-N 0.000 description 1
- CSTDQOOBZBAJKE-BWAGICSOSA-N His-Tyr-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)NC(=O)[C@H](CC2=CN=CN2)N)O CSTDQOOBZBAJKE-BWAGICSOSA-N 0.000 description 1
- NZGTYCMLUGYMCV-XUXIUFHCSA-N Ile-Lys-Arg Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)N NZGTYCMLUGYMCV-XUXIUFHCSA-N 0.000 description 1
- JHNJNTMTZHEDLJ-NAKRPEOUSA-N Ile-Ser-Arg Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O JHNJNTMTZHEDLJ-NAKRPEOUSA-N 0.000 description 1
- VGSPNSSCMOHRRR-BJDJZHNGSA-N Ile-Ser-Lys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)O)N VGSPNSSCMOHRRR-BJDJZHNGSA-N 0.000 description 1
- ANTFEOSJMAUGIB-KNZXXDILSA-N Ile-Thr-Pro Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H]([C@@H](C)O)C(=O)N1CCC[C@@H]1C(=O)O)N ANTFEOSJMAUGIB-KNZXXDILSA-N 0.000 description 1
- 108060003951 Immunoglobulin Proteins 0.000 description 1
- 102000008394 Immunoglobulin Fragments Human genes 0.000 description 1
- 108010021625 Immunoglobulin Fragments Proteins 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- RCFDOSNHHZGBOY-UHFFFAOYSA-N L-isoleucyl-L-alanine Natural products CCC(C)C(N)C(=O)NC(C)C(O)=O RCFDOSNHHZGBOY-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-M L-tartrate(1-) Chemical compound OC(=O)[C@H](O)[C@@H](O)C([O-])=O FEWJPZIEWOKRBE-JCYAYHJZSA-M 0.000 description 1
- WSGXUIQTEZDVHJ-GARJFASQSA-N Leu-Ala-Pro Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](C)C(=O)N1CCC[C@@H]1C(O)=O WSGXUIQTEZDVHJ-GARJFASQSA-N 0.000 description 1
- OIARJGNVARWKFP-YUMQZZPRSA-N Leu-Asn-Gly Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(O)=O OIARJGNVARWKFP-YUMQZZPRSA-N 0.000 description 1
- PVMPDMIKUVNOBD-CIUDSAMLSA-N Leu-Asp-Ser Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(O)=O PVMPDMIKUVNOBD-CIUDSAMLSA-N 0.000 description 1
- KAFOIVJDVSZUMD-DCAQKATOSA-N Leu-Gln-Gln Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(O)=O KAFOIVJDVSZUMD-DCAQKATOSA-N 0.000 description 1
- KAFOIVJDVSZUMD-UHFFFAOYSA-N Leu-Gln-Gln Natural products CC(C)CC(N)C(=O)NC(CCC(N)=O)C(=O)NC(CCC(N)=O)C(O)=O KAFOIVJDVSZUMD-UHFFFAOYSA-N 0.000 description 1
- RSFGIMMPWAXNML-MNXVOIDGSA-N Leu-Gln-Ile Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O RSFGIMMPWAXNML-MNXVOIDGSA-N 0.000 description 1
- CQGSYZCULZMEDE-UHFFFAOYSA-N Leu-Gln-Pro Natural products CC(C)CC(N)C(=O)NC(CCC(N)=O)C(=O)N1CCCC1C(O)=O CQGSYZCULZMEDE-UHFFFAOYSA-N 0.000 description 1
- GPICTNQYKHHHTH-GUBZILKMSA-N Leu-Gln-Ser Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(O)=O GPICTNQYKHHHTH-GUBZILKMSA-N 0.000 description 1
- BTNXKBVLWJBTNR-SRVKXCTJSA-N Leu-His-Asn Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CC(N)=O)C(O)=O BTNXKBVLWJBTNR-SRVKXCTJSA-N 0.000 description 1
- IAJFFZORSWOZPQ-SRVKXCTJSA-N Leu-Leu-Asn Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(O)=O IAJFFZORSWOZPQ-SRVKXCTJSA-N 0.000 description 1
- VCHVSKNMTXWIIP-SRVKXCTJSA-N Leu-Lys-Ser Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(O)=O VCHVSKNMTXWIIP-SRVKXCTJSA-N 0.000 description 1
- FIICHHJDINDXKG-IHPCNDPISA-N Leu-Lys-Trp Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(O)=O FIICHHJDINDXKG-IHPCNDPISA-N 0.000 description 1
- XOWMDXHFSBCAKQ-SRVKXCTJSA-N Leu-Ser-Leu Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CC(C)C XOWMDXHFSBCAKQ-SRVKXCTJSA-N 0.000 description 1
- BRTVHXHCUSXYRI-CIUDSAMLSA-N Leu-Ser-Ser Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(O)=O BRTVHXHCUSXYRI-CIUDSAMLSA-N 0.000 description 1
- LINKCQUOMUDLKN-KATARQTJSA-N Leu-Thr-Cys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CC(C)C)N)O LINKCQUOMUDLKN-KATARQTJSA-N 0.000 description 1
- LCNASHSOFMRYFO-WDCWCFNPSA-N Leu-Thr-Gln Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@H](C(O)=O)CCC(N)=O LCNASHSOFMRYFO-WDCWCFNPSA-N 0.000 description 1
- ILDSIMPXNFWKLH-KATARQTJSA-N Leu-Thr-Ser Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(O)=O ILDSIMPXNFWKLH-KATARQTJSA-N 0.000 description 1
- AIQWYVFNBNNOLU-RHYQMDGZSA-N Leu-Thr-Val Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(O)=O AIQWYVFNBNNOLU-RHYQMDGZSA-N 0.000 description 1
- VUBIPAHVHMZHCM-KKUMJFAQSA-N Leu-Tyr-Ser Chemical compound CC(C)C[C@H](N)C(=O)N[C@H](C(=O)N[C@@H](CO)C(O)=O)CC1=CC=C(O)C=C1 VUBIPAHVHMZHCM-KKUMJFAQSA-N 0.000 description 1
- YQFZRHYZLARWDY-IHRRRGAJSA-N Leu-Val-Lys Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(O)=O)CCCCN YQFZRHYZLARWDY-IHRRRGAJSA-N 0.000 description 1
- QESXLSQLQHHTIX-RHYQMDGZSA-N Leu-Val-Thr Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O QESXLSQLQHHTIX-RHYQMDGZSA-N 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- KCXUCYYZNZFGLL-SRVKXCTJSA-N Lys-Ala-Leu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(O)=O KCXUCYYZNZFGLL-SRVKXCTJSA-N 0.000 description 1
- IXHKPDJKKCUKHS-GARJFASQSA-N Lys-Ala-Pro Chemical compound C[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CCCCN)N IXHKPDJKKCUKHS-GARJFASQSA-N 0.000 description 1
- UWKNTTJNVSYXPC-CIUDSAMLSA-N Lys-Ala-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CCCCN UWKNTTJNVSYXPC-CIUDSAMLSA-N 0.000 description 1
- NTBFKPBULZGXQL-KKUMJFAQSA-N Lys-Asp-Tyr Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 NTBFKPBULZGXQL-KKUMJFAQSA-N 0.000 description 1
- MWVUEPNEPWMFBD-SRVKXCTJSA-N Lys-Cys-Lys Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](CS)C(=O)N[C@H](C(O)=O)CCCCN MWVUEPNEPWMFBD-SRVKXCTJSA-N 0.000 description 1
- ODUQLUADRKMHOZ-JYJNAYRXSA-N Lys-Glu-Tyr Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CCCCN)N)O ODUQLUADRKMHOZ-JYJNAYRXSA-N 0.000 description 1
- GQZMPWBZQALKJO-UWVGGRQHSA-N Lys-Gly-Arg Chemical compound [H]N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(O)=O GQZMPWBZQALKJO-UWVGGRQHSA-N 0.000 description 1
- RFQATBGBLDAKGI-VHSXEESVSA-N Lys-Gly-Pro Chemical compound C1C[C@@H](N(C1)C(=O)CNC(=O)[C@H](CCCCN)N)C(=O)O RFQATBGBLDAKGI-VHSXEESVSA-N 0.000 description 1
- AIRZWUMAHCDDHR-KKUMJFAQSA-N Lys-Leu-Leu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O AIRZWUMAHCDDHR-KKUMJFAQSA-N 0.000 description 1
- LUTDBHBIHHREDC-IHRRRGAJSA-N Lys-Pro-Lys Chemical compound NCCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCCN)C(O)=O LUTDBHBIHHREDC-IHRRRGAJSA-N 0.000 description 1
- YTJFXEDRUOQGSP-DCAQKATOSA-N Lys-Pro-Ser Chemical compound [H]N[C@@H](CCCCN)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O YTJFXEDRUOQGSP-DCAQKATOSA-N 0.000 description 1
- YKBSXQFZWFXFIB-VOAKCMCISA-N Lys-Thr-Lys Chemical compound NCCCC[C@H](N)C(=O)N[C@@H]([C@H](O)C)C(=O)N[C@@H](CCCCN)C(O)=O YKBSXQFZWFXFIB-VOAKCMCISA-N 0.000 description 1
- XABXVVSWUVCZST-GVXVVHGQSA-N Lys-Val-Gln Chemical compound NC(=O)CC[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](N)CCCCN XABXVVSWUVCZST-GVXVVHGQSA-N 0.000 description 1
- UGCIQUYEJIEHKX-GVXVVHGQSA-N Lys-Val-Glu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O UGCIQUYEJIEHKX-GVXVVHGQSA-N 0.000 description 1
- PEEHTFAAVSWFBL-UHFFFAOYSA-N Maleimide Chemical compound O=C1NC(=O)C=C1 PEEHTFAAVSWFBL-UHFFFAOYSA-N 0.000 description 1
- IHRFZLQEQVHXFA-RHYQMDGZSA-N Met-Thr-Lys Chemical compound CSCC[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@H](C(O)=O)CCCCN IHRFZLQEQVHXFA-RHYQMDGZSA-N 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 108091028043 Nucleic acid sequence Proteins 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- LRBQNJMCXXYXIU-PPKXGCFTSA-N Penta-digallate-beta-D-glucose Natural products OC1=C(O)C(O)=CC(C(=O)OC=2C(=C(O)C=C(C=2)C(=O)OC[C@@H]2[C@H]([C@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)O2)OC(=O)C=2C=C(OC(=O)C=3C=C(O)C(O)=C(O)C=3)C(O)=C(O)C=2)O)=C1 LRBQNJMCXXYXIU-PPKXGCFTSA-N 0.000 description 1
- 102000035195 Peptidases Human genes 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- LBSARGIQACMGDF-WBAXXEDZSA-N Phe-Ala-Phe Chemical compound C([C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CC=CC=C1 LBSARGIQACMGDF-WBAXXEDZSA-N 0.000 description 1
- HXSUFWQYLPKEHF-IHRRRGAJSA-N Phe-Asn-Arg Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)N HXSUFWQYLPKEHF-IHRRRGAJSA-N 0.000 description 1
- JOXIIFVCSATTDH-IHPCNDPISA-N Phe-Asn-Trp Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CC2=CNC3=CC=CC=C32)C(=O)O)N JOXIIFVCSATTDH-IHPCNDPISA-N 0.000 description 1
- BIYWZVCPZIFGPY-QWRGUYRKSA-N Phe-Gly-Ser Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)NCC(=O)N[C@@H](CO)C(O)=O BIYWZVCPZIFGPY-QWRGUYRKSA-N 0.000 description 1
- BWTKUQPNOMMKMA-FIRPJDEBSA-N Phe-Ile-Phe Chemical compound C([C@H](N)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CC=CC=C1 BWTKUQPNOMMKMA-FIRPJDEBSA-N 0.000 description 1
- JDMKQHSHKJHAHR-UHFFFAOYSA-N Phe-Phe-Leu-Tyr Natural products C=1C=C(O)C=CC=1CC(C(O)=O)NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)CC1=CC=CC=C1 JDMKQHSHKJHAHR-UHFFFAOYSA-N 0.000 description 1
- QARPMYDMYVLFMW-KKUMJFAQSA-N Phe-Pro-Glu Chemical compound C([C@H](N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(O)=O)C(O)=O)C1=CC=CC=C1 QARPMYDMYVLFMW-KKUMJFAQSA-N 0.000 description 1
- ZJPGOXWRFNKIQL-JYJNAYRXSA-N Phe-Pro-Pro Chemical compound C([C@H](N)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(O)=O)C1=CC=CC=C1 ZJPGOXWRFNKIQL-JYJNAYRXSA-N 0.000 description 1
- JHSRGEODDALISP-XVSYOHENSA-N Phe-Thr-Asn Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(O)=O JHSRGEODDALISP-XVSYOHENSA-N 0.000 description 1
- KLYYKKGCPOGDPE-OEAJRASXSA-N Phe-Thr-Leu Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(O)=O KLYYKKGCPOGDPE-OEAJRASXSA-N 0.000 description 1
- SJRQWEDYTKYHHL-SLFFLAALSA-N Phe-Tyr-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC2=CC=C(C=C2)O)NC(=O)[C@H](CC3=CC=CC=C3)N)C(=O)O SJRQWEDYTKYHHL-SLFFLAALSA-N 0.000 description 1
- UAYHMOIGIQZLFR-NHCYSSNCSA-N Pro-Gln-Val Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C(C)C)C(O)=O UAYHMOIGIQZLFR-NHCYSSNCSA-N 0.000 description 1
- KIPIKSXPPLABPN-CIUDSAMLSA-N Pro-Glu-Asn Chemical compound NC(=O)C[C@@H](C(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H]1CCCN1 KIPIKSXPPLABPN-CIUDSAMLSA-N 0.000 description 1
- UIMCLYYSUCIUJM-UWVGGRQHSA-N Pro-Gly-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H]1CCCN1 UIMCLYYSUCIUJM-UWVGGRQHSA-N 0.000 description 1
- MHHQQZIFLWFZGR-DCAQKATOSA-N Pro-Lys-Ser Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(O)=O MHHQQZIFLWFZGR-DCAQKATOSA-N 0.000 description 1
- HWLKHNDRXWTFTN-GUBZILKMSA-N Pro-Pro-Cys Chemical compound C1C[C@H](NC1)C(=O)N2CCC[C@H]2C(=O)N[C@@H](CS)C(=O)O HWLKHNDRXWTFTN-GUBZILKMSA-N 0.000 description 1
- MKGIILKDUGDRRO-FXQIFTODSA-N Pro-Ser-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H]1CCCN1 MKGIILKDUGDRRO-FXQIFTODSA-N 0.000 description 1
- PRKWBYCXBBSLSK-GUBZILKMSA-N Pro-Ser-Val Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O PRKWBYCXBBSLSK-GUBZILKMSA-N 0.000 description 1
- VVAWNPIOYXAMAL-KJEVXHAQSA-N Pro-Thr-Tyr Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O VVAWNPIOYXAMAL-KJEVXHAQSA-N 0.000 description 1
- YDTUEBLEAVANFH-RCWTZXSCSA-N Pro-Val-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H]1CCCN1 YDTUEBLEAVANFH-RCWTZXSCSA-N 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- QPFJSHSJFIYDJZ-GHCJXIJMSA-N Ser-Asp-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](N)CO QPFJSHSJFIYDJZ-GHCJXIJMSA-N 0.000 description 1
- ULVMNZOKDBHKKI-ACZMJKKPSA-N Ser-Gln-Asp Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O ULVMNZOKDBHKKI-ACZMJKKPSA-N 0.000 description 1
- UQFYNFTYDHUIMI-WHFBIAKZSA-N Ser-Gly-Ala Chemical compound OC(=O)[C@H](C)NC(=O)CNC(=O)[C@@H](N)CO UQFYNFTYDHUIMI-WHFBIAKZSA-N 0.000 description 1
- ZOPISOXXPQNOCO-SVSWQMSJSA-N Ser-Ile-Thr Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H]([C@@H](C)O)C(=O)O)NC(=O)[C@H](CO)N ZOPISOXXPQNOCO-SVSWQMSJSA-N 0.000 description 1
- NLOAIFSWUUFQFR-CIUDSAMLSA-N Ser-Leu-Asp Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(O)=O NLOAIFSWUUFQFR-CIUDSAMLSA-N 0.000 description 1
- GJFYFGOEWLDQGW-GUBZILKMSA-N Ser-Leu-Gln Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](CO)N GJFYFGOEWLDQGW-GUBZILKMSA-N 0.000 description 1
- XNCUYZKGQOCOQH-YUMQZZPRSA-N Ser-Leu-Gly Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)NCC(O)=O XNCUYZKGQOCOQH-YUMQZZPRSA-N 0.000 description 1
- YUJLIIRMIAGMCQ-CIUDSAMLSA-N Ser-Leu-Ser Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(O)=O YUJLIIRMIAGMCQ-CIUDSAMLSA-N 0.000 description 1
- AZWNCEBQZXELEZ-FXQIFTODSA-N Ser-Pro-Ser Chemical compound OC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O AZWNCEBQZXELEZ-FXQIFTODSA-N 0.000 description 1
- SRSPTFBENMJHMR-WHFBIAKZSA-N Ser-Ser-Gly Chemical compound OC[C@H](N)C(=O)N[C@@H](CO)C(=O)NCC(O)=O SRSPTFBENMJHMR-WHFBIAKZSA-N 0.000 description 1
- BMKNXTJLHFIAAH-CIUDSAMLSA-N Ser-Ser-Leu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(O)=O BMKNXTJLHFIAAH-CIUDSAMLSA-N 0.000 description 1
- OZPDGESCTGGNAD-CIUDSAMLSA-N Ser-Ser-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CO OZPDGESCTGGNAD-CIUDSAMLSA-N 0.000 description 1
- CUXJENOFJXOSOZ-BIIVOSGPSA-N Ser-Ser-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CO)NC(=O)[C@H](CO)N)C(=O)O CUXJENOFJXOSOZ-BIIVOSGPSA-N 0.000 description 1
- XJDMUQCLVSCRSJ-VZFHVOOUSA-N Ser-Thr-Ala Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C)C(O)=O XJDMUQCLVSCRSJ-VZFHVOOUSA-N 0.000 description 1
- NADLKBTYNKUJEP-KATARQTJSA-N Ser-Thr-Leu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(O)=O NADLKBTYNKUJEP-KATARQTJSA-N 0.000 description 1
- SNXUIBACCONSOH-BWBBJGPYSA-N Ser-Thr-Ser Chemical compound OC[C@H](N)C(=O)N[C@@H]([C@H](O)C)C(=O)N[C@@H](CO)C(O)=O SNXUIBACCONSOH-BWBBJGPYSA-N 0.000 description 1
- AXKJPUBALUNJEO-UBHSHLNASA-N Ser-Trp-Asn Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](CC(N)=O)C(O)=O AXKJPUBALUNJEO-UBHSHLNASA-N 0.000 description 1
- FGBLCMLXHRPVOF-IHRRRGAJSA-N Ser-Tyr-Arg Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O FGBLCMLXHRPVOF-IHRRRGAJSA-N 0.000 description 1
- BIWBTRRBHIEVAH-IHPCNDPISA-N Ser-Tyr-Trp Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(O)=O BIWBTRRBHIEVAH-IHPCNDPISA-N 0.000 description 1
- LGIMRDKGABDMBN-DCAQKATOSA-N Ser-Val-Lys Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CO)N LGIMRDKGABDMBN-DCAQKATOSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 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 1
- PZBFGYYEXUXCOF-UHFFFAOYSA-N TCEP Chemical compound OC(=O)CCP(CCC(O)=O)CCC(O)=O PZBFGYYEXUXCOF-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- DWYAUVCQDTZIJI-VZFHVOOUSA-N Thr-Ala-Ser Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(O)=O DWYAUVCQDTZIJI-VZFHVOOUSA-N 0.000 description 1
- YOSLMIPKOUAHKI-OLHMAJIHSA-N Thr-Asp-Asp Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O YOSLMIPKOUAHKI-OLHMAJIHSA-N 0.000 description 1
- KGKWKSSSQGGYAU-SUSMZKCASA-N Thr-Gln-Thr Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H]([C@@H](C)O)C(=O)O)N)O KGKWKSSSQGGYAU-SUSMZKCASA-N 0.000 description 1
- GKWNLDNXMMLRMC-GLLZPBPUSA-N Thr-Glu-Gln Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N)O GKWNLDNXMMLRMC-GLLZPBPUSA-N 0.000 description 1
- AQAMPXBRJJWPNI-JHEQGTHGSA-N Thr-Gly-Glu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(O)=O AQAMPXBRJJWPNI-JHEQGTHGSA-N 0.000 description 1
- FQPDRTDDEZXCEC-SVSWQMSJSA-N Thr-Ile-Ser Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(O)=O FQPDRTDDEZXCEC-SVSWQMSJSA-N 0.000 description 1
- YOOAQCZYZHGUAZ-KATARQTJSA-N Thr-Leu-Ser Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(O)=O YOOAQCZYZHGUAZ-KATARQTJSA-N 0.000 description 1
- BIBYEFRASCNLAA-CDMKHQONSA-N Thr-Phe-Gly Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@H](C(=O)NCC(O)=O)CC1=CC=CC=C1 BIBYEFRASCNLAA-CDMKHQONSA-N 0.000 description 1
- JMBRNXUOLJFURW-BEAPCOKYSA-N Thr-Phe-Pro Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N2CCC[C@@H]2C(=O)O)N)O JMBRNXUOLJFURW-BEAPCOKYSA-N 0.000 description 1
- XKWABWFMQXMUMT-HJGDQZAQSA-N Thr-Pro-Glu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(O)=O XKWABWFMQXMUMT-HJGDQZAQSA-N 0.000 description 1
- IEZVHOULSUULHD-XGEHTFHBSA-N Thr-Ser-Val Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O IEZVHOULSUULHD-XGEHTFHBSA-N 0.000 description 1
- ZESGVALRVJIVLZ-VFCFLDTKSA-N Thr-Thr-Pro Chemical compound C[C@H]([C@@H](C(=O)N[C@@H]([C@@H](C)O)C(=O)N1CCC[C@@H]1C(=O)O)N)O ZESGVALRVJIVLZ-VFCFLDTKSA-N 0.000 description 1
- OGOYMQWIWHGTGH-KZVJFYERSA-N Thr-Val-Ala Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C)C(O)=O OGOYMQWIWHGTGH-KZVJFYERSA-N 0.000 description 1
- 102100023935 Transmembrane glycoprotein NMB Human genes 0.000 description 1
- UDCHKDYNMRJYMI-QEJZJMRPSA-N Trp-Glu-Ser Chemical compound [H]N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(O)=O UDCHKDYNMRJYMI-QEJZJMRPSA-N 0.000 description 1
- NLWCSMOXNKBRLC-WDSOQIARSA-N Trp-Lys-Val Chemical compound [H]N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(O)=O NLWCSMOXNKBRLC-WDSOQIARSA-N 0.000 description 1
- UOXPLPBMEPLZBW-WDSOQIARSA-N Trp-Val-Lys Chemical compound C1=CC=C2C(C[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(O)=O)=CNC2=C1 UOXPLPBMEPLZBW-WDSOQIARSA-N 0.000 description 1
- QOIKZODVIPOPDD-AVGNSLFASA-N Tyr-Cys-Gln Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(O)=O QOIKZODVIPOPDD-AVGNSLFASA-N 0.000 description 1
- QUILOGWWLXMSAT-IHRRRGAJSA-N Tyr-Gln-Gln Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(O)=O QUILOGWWLXMSAT-IHRRRGAJSA-N 0.000 description 1
- SLCSPPCQWUHPPO-JYJNAYRXSA-N Tyr-Glu-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 SLCSPPCQWUHPPO-JYJNAYRXSA-N 0.000 description 1
- JJNXZIPLIXIGBX-HJPIBITLSA-N Tyr-Ile-Cys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)N JJNXZIPLIXIGBX-HJPIBITLSA-N 0.000 description 1
- LMKKMCGTDANZTR-BZSNNMDCSA-N Tyr-Phe-Asp Chemical compound C([C@H](N)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC(O)=O)C(O)=O)C1=CC=C(O)C=C1 LMKKMCGTDANZTR-BZSNNMDCSA-N 0.000 description 1
- VYQQQIRHIFALGE-UWJYBYFXSA-N Tyr-Ser-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 VYQQQIRHIFALGE-UWJYBYFXSA-N 0.000 description 1
- MQGGXGKQSVEQHR-KKUMJFAQSA-N Tyr-Ser-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 MQGGXGKQSVEQHR-KKUMJFAQSA-N 0.000 description 1
- NHOVZGFNTGMYMI-KKUMJFAQSA-N Tyr-Ser-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 NHOVZGFNTGMYMI-KKUMJFAQSA-N 0.000 description 1
- ZZDYJFVIKVSUFA-WLTAIBSBSA-N Tyr-Thr-Gly Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(O)=O ZZDYJFVIKVSUFA-WLTAIBSBSA-N 0.000 description 1
- PWKMJDQXKCENMF-MEYUZBJRSA-N Tyr-Thr-Leu Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(O)=O PWKMJDQXKCENMF-MEYUZBJRSA-N 0.000 description 1
- SQUMHUZLJDUROQ-YDHLFZDLSA-N Tyr-Val-Asp Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(O)=O)C(O)=O SQUMHUZLJDUROQ-YDHLFZDLSA-N 0.000 description 1
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 1
- VJOWWOGRNXRQMF-UVBJJODRSA-N Val-Ala-Trp Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@H](C)NC(=O)[C@@H](N)C(C)C)C(O)=O)=CNC2=C1 VJOWWOGRNXRQMF-UVBJJODRSA-N 0.000 description 1
- BMGOFDMKDVVGJG-NHCYSSNCSA-N Val-Asp-Lys Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CCCCN)C(=O)O)N BMGOFDMKDVVGJG-NHCYSSNCSA-N 0.000 description 1
- HGJRMXOWUWVUOA-GVXVVHGQSA-N Val-Leu-Gln Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](C(C)C)N HGJRMXOWUWVUOA-GVXVVHGQSA-N 0.000 description 1
- XTDDIVQWDXMRJL-IHRRRGAJSA-N Val-Leu-His Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)NC(=O)[C@H](C(C)C)N XTDDIVQWDXMRJL-IHRRRGAJSA-N 0.000 description 1
- SYSWVVCYSXBVJG-RHYQMDGZSA-N Val-Leu-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C(C)C)N)O SYSWVVCYSXBVJG-RHYQMDGZSA-N 0.000 description 1
- HJSLDXZAZGFPDK-ULQDDVLXSA-N Val-Phe-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=CC=C1)NC(=O)[C@H](C(C)C)N HJSLDXZAZGFPDK-ULQDDVLXSA-N 0.000 description 1
- VCIYTVOBLZHFSC-XHSDSOJGSA-N Val-Phe-Pro Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N2CCC[C@@H]2C(=O)O)N VCIYTVOBLZHFSC-XHSDSOJGSA-N 0.000 description 1
- KISFXYYRKKNLOP-IHRRRGAJSA-N Val-Phe-Ser Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(=O)O)N KISFXYYRKKNLOP-IHRRRGAJSA-N 0.000 description 1
- ZXYPHBKIZLAQTL-QXEWZRGKSA-N Val-Pro-Asp Chemical compound CC(C)[C@@H](C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(=O)O)C(=O)O)N ZXYPHBKIZLAQTL-QXEWZRGKSA-N 0.000 description 1
- KSFXWENSJABBFI-ZKWXMUAHSA-N Val-Ser-Asn Chemical compound [H]N[C@@H](C(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(O)=O KSFXWENSJABBFI-ZKWXMUAHSA-N 0.000 description 1
- JQTYTBPCSOAZHI-FXQIFTODSA-N Val-Ser-Cys Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CS)C(=O)O)N JQTYTBPCSOAZHI-FXQIFTODSA-N 0.000 description 1
- KRAHMIJVUPUOTQ-DCAQKATOSA-N Val-Ser-His Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)N KRAHMIJVUPUOTQ-DCAQKATOSA-N 0.000 description 1
- PGQUDQYHWICSAB-NAKRPEOUSA-N Val-Ser-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H](C(C)C)N PGQUDQYHWICSAB-NAKRPEOUSA-N 0.000 description 1
- PZTZYZUTCPZWJH-FXQIFTODSA-N Val-Ser-Ser Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)O)N PZTZYZUTCPZWJH-FXQIFTODSA-N 0.000 description 1
- BZDGLJPROOOUOZ-XGEHTFHBSA-N Val-Thr-Cys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](C(C)C)N)O BZDGLJPROOOUOZ-XGEHTFHBSA-N 0.000 description 1
- TVGWMCTYUFBXAP-QTKMDUPCSA-N Val-Thr-His Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)NC(=O)[C@H](C(C)C)N)O TVGWMCTYUFBXAP-QTKMDUPCSA-N 0.000 description 1
- GVNLOVJNNDZUHS-RHYQMDGZSA-N Val-Thr-Lys Chemical compound [H]N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(O)=O GVNLOVJNNDZUHS-RHYQMDGZSA-N 0.000 description 1
- QHSSPPHOHJSTML-HOCLYGCPSA-N Val-Trp-Gly Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)NCC(=O)O)N QHSSPPHOHJSTML-HOCLYGCPSA-N 0.000 description 1
- PGBMPFKFKXYROZ-UFYCRDLUSA-N Val-Tyr-Phe Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)N[C@@H](CC2=CC=CC=C2)C(=O)O)N PGBMPFKFKXYROZ-UFYCRDLUSA-N 0.000 description 1
- ZLNYBMWGPOKSLW-LSJOCFKGSA-N Val-Val-Asp Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(O)=O)C(O)=O ZLNYBMWGPOKSLW-LSJOCFKGSA-N 0.000 description 1
- ZHWZDZFWBXWPDW-GUBZILKMSA-N Val-Val-Cys Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CS)C(O)=O ZHWZDZFWBXWPDW-GUBZILKMSA-N 0.000 description 1
- LLJLBRRXKZTTRD-GUBZILKMSA-N Val-Val-Ser Chemical compound CC(C)[C@@H](C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CO)C(=O)O)N LLJLBRRXKZTTRD-GUBZILKMSA-N 0.000 description 1
- JVGDAEKKZKKZFO-RCWTZXSCSA-N Val-Val-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](C(C)C)N)O JVGDAEKKZKKZFO-RCWTZXSCSA-N 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 238000001042 affinity chromatography Methods 0.000 description 1
- 229960003767 alanine Drugs 0.000 description 1
- 108010069020 alanyl-prolyl-glycine Proteins 0.000 description 1
- 108010086434 alanyl-seryl-glycine Proteins 0.000 description 1
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical class [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 229940024606 amino acid Drugs 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 229940125644 antibody drug Drugs 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 108010009111 arginyl-glycyl-glutamic acid Proteins 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 108010069205 aspartyl-phenylalanine Proteins 0.000 description 1
- 108010047857 aspartylglycine Proteins 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- ACBQROXDOHKANW-UHFFFAOYSA-N bis(4-nitrophenyl) carbonate Chemical compound C1=CC([N+](=O)[O-])=CC=C1OC(=O)OC1=CC=C([N+]([O-])=O)C=C1 ACBQROXDOHKANW-UHFFFAOYSA-N 0.000 description 1
- 150000001621 bismuth Chemical class 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 229940098773 bovine serum albumin Drugs 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 230000028956 calcium-mediated signaling Effects 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 239000006143 cell culture medium Substances 0.000 description 1
- 238000003570 cell viability assay Methods 0.000 description 1
- 201000010881 cervical cancer Diseases 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 238000012412 chemical coupling Methods 0.000 description 1
- 239000007979 citrate buffer Substances 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 239000004020 conductor Substances 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000012045 crude solution Substances 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000006547 cyclononyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 231100000599 cytotoxic agent Toxicity 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical class OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 239000012470 diluted sample Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- UXGNZZKBCMGWAZ-UHFFFAOYSA-N dimethylformamide dmf Chemical compound CN(C)C=O.CN(C)C=O UXGNZZKBCMGWAZ-UHFFFAOYSA-N 0.000 description 1
- IZEKFCXSFNUWAM-UHFFFAOYSA-N dipyridamole Chemical compound C=12N=C(N(CCO)CCO)N=C(N3CCCCC3)C2=NC(N(CCO)CCO)=NC=1N1CCCCC1 IZEKFCXSFNUWAM-UHFFFAOYSA-N 0.000 description 1
- 229960002768 dipyridamole Drugs 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- VHJLVAABSRFDPM-QWWZWVQMSA-N dithiothreitol Chemical compound SC[C@@H](O)[C@H](O)CS VHJLVAABSRFDPM-QWWZWVQMSA-N 0.000 description 1
- CETRZFQIITUQQL-UHFFFAOYSA-N dmso dimethylsulfoxide Chemical compound CS(C)=O.CS(C)=O CETRZFQIITUQQL-UHFFFAOYSA-N 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 229960001484 edetic acid Drugs 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 239000013604 expression vector Substances 0.000 description 1
- 238000010812 external standard method Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 238000001506 fluorescence spectroscopy Methods 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 229960002598 fumaric acid Drugs 0.000 description 1
- LRBQNJMCXXYXIU-QWKBTXIPSA-N gallotannic acid Chemical compound OC1=C(O)C(O)=CC(C(=O)OC=2C(=C(O)C=C(C=2)C(=O)OC[C@H]2[C@@H]([C@@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)O2)OC(=O)C=2C=C(OC(=O)C=3C=C(O)C(O)=C(O)C=3)C(O)=C(O)C=2)O)=C1 LRBQNJMCXXYXIU-QWKBTXIPSA-N 0.000 description 1
- 229960005219 gentisic acid Drugs 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 229950006191 gluconic acid Drugs 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 108010013768 glutamyl-aspartyl-proline Proteins 0.000 description 1
- 108010049041 glutamylalanine Proteins 0.000 description 1
- 108010000434 glycyl-alanyl-leucine Proteins 0.000 description 1
- 108010050475 glycyl-leucyl-tyrosine Proteins 0.000 description 1
- 108010077435 glycyl-phenylalanyl-glycine Proteins 0.000 description 1
- 108010050848 glycylleucine Proteins 0.000 description 1
- 108010015792 glycyllysine Proteins 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 238000003306 harvesting Methods 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 210000004408 hybridoma Anatomy 0.000 description 1
- 150000007857 hydrazones Chemical class 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- 102000018358 immunoglobulin Human genes 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 229960004768 irinotecan Drugs 0.000 description 1
- 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 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 108010034529 leucyl-lysine Proteins 0.000 description 1
- 108010073472 leucyl-prolyl-proline Proteins 0.000 description 1
- 108010057821 leucylproline Proteins 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 229910003002 lithium salt Inorganic materials 0.000 description 1
- 159000000002 lithium salts Chemical class 0.000 description 1
- 238000004020 luminiscence type Methods 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 235000018977 lysine Nutrition 0.000 description 1
- 125000003588 lysine group Chemical class [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
- 230000002132 lysosomal effect Effects 0.000 description 1
- 210000003712 lysosome Anatomy 0.000 description 1
- 230000001868 lysosomic effect Effects 0.000 description 1
- 108010003700 lysyl aspartic acid Proteins 0.000 description 1
- 239000012516 mab select resin Substances 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 229960002969 oleic acid Drugs 0.000 description 1
- 235000021313 oleic acid Nutrition 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 239000011713 pantothenic acid Substances 0.000 description 1
- 229940055726 pantothenic acid Drugs 0.000 description 1
- 235000019161 pantothenic acid Nutrition 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 238000002823 phage display Methods 0.000 description 1
- 108010024654 phenylalanyl-prolyl-alanine Proteins 0.000 description 1
- 108010051242 phenylalanylserine Proteins 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 239000013612 plasmid Substances 0.000 description 1
- 238000003752 polymerase chain reaction Methods 0.000 description 1
- 108091033319 polynucleotide Proteins 0.000 description 1
- 239000002157 polynucleotide Substances 0.000 description 1
- 102000040430 polynucleotide Human genes 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 108010077112 prolyl-proline Proteins 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 238000006578 reductive coupling reaction Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 239000012488 sample solution Substances 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000012163 sequencing technique Methods 0.000 description 1
- 108010069117 seryl-lysyl-aspartic acid Proteins 0.000 description 1
- 108010048397 seryl-lysyl-leucine Proteins 0.000 description 1
- 102000034285 signal transducing proteins Human genes 0.000 description 1
- 108091006024 signal transducing proteins Proteins 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229940126586 small molecule drug Drugs 0.000 description 1
- 239000000878 small molecule-drug conjugate Substances 0.000 description 1
- BHZOKUMUHVTPBX-UHFFFAOYSA-M sodium acetic acid acetate Chemical compound [Na+].CC(O)=O.CC([O-])=O BHZOKUMUHVTPBX-UHFFFAOYSA-M 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000001502 supplementing effect Effects 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 235000015523 tannic acid Nutrition 0.000 description 1
- 229920002258 tannic acid Polymers 0.000 description 1
- 229940033123 tannic acid Drugs 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 229960001367 tartaric acid Drugs 0.000 description 1
- ISIJQEHRDSCQIU-UHFFFAOYSA-N tert-butyl 2,7-diazaspiro[4.5]decane-7-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC11CNCC1 ISIJQEHRDSCQIU-UHFFFAOYSA-N 0.000 description 1
- 238000011287 therapeutic dose Methods 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 108010071097 threonyl-lysyl-proline Proteins 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- 230000001131 transforming effect Effects 0.000 description 1
- 108091007466 transmembrane glycoproteins Proteins 0.000 description 1
- 210000002993 trophoblast Anatomy 0.000 description 1
- 108010080629 tryptophan-leucine Proteins 0.000 description 1
- 108010051110 tyrosyl-lysine Proteins 0.000 description 1
- 108010071635 tyrosyl-prolyl-arginine Proteins 0.000 description 1
- 238000000108 ultra-filtration Methods 0.000 description 1
- 108010052774 valyl-lysyl-glycyl-phenylalanyl-tyrosine Proteins 0.000 description 1
- 108010073969 valyllysine Proteins 0.000 description 1
- 239000013598 vector Substances 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
Images
Classifications
-
- 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
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
- A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
-
- 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
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
-
- 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
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
- A61K47/6849—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a receptor, a cell surface antigen or a cell surface determinant
-
- 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
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6889—Conjugates wherein the antibody being the modifying agent and wherein the linker, binder or spacer confers particular properties to the conjugates, e.g. peptidic enzyme-labile linkers or acid-labile linkers, providing for an acid-labile immuno conjugate wherein the drug may be released from its antibody conjugated part in an acidic, e.g. tumoural or environment
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Epidemiology (AREA)
- Immunology (AREA)
- Cell Biology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Peptides Or Proteins (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
本发明公开了一种靶向TROP2的抗体药物偶联物、制备方法及应用。本发明提供了一种如式I所示的抗体药物偶联物,该类化合物具有很好的靶向性,对阳性表达TROP2的肿瘤细胞具有很好的抑制效果,并且,具有很好的成药性,安全性高。该抗体药物偶联物具有TROP2的抑制效果,还对NCI‑N87、MDA‑MB‑468和BXPC3细胞中的至少一种有良好的抑制效果。
Description
技术领域
本发明涉及生物医药领域,尤其涉及一种靶向TROP2的抗体药物偶联物、其制备方法及应用。
背景技术
肿瘤相关钙信号传导蛋白2(Trop2,TROP2)是TACSTD2基因编码的一型跨膜糖蛋白,是钙信号传导子与细胞内钙信号调节相关,Trop2表达可以活化ERK,正常情况下Trop2主要表达于滋养层细胞,并在胚胎器官发育过程中起重要作用。在许多人上皮来源肿瘤组织过表达,包括乳腺癌、肺癌、胃癌、结直肠癌、胰腺癌、前列腺癌,子宫颈癌,卵巢癌等,表达水平与肿瘤的恶化及预后相关。乳腺癌患者基因组分析及目前的临床研究结果表明,Trop2是一个经临床确证了的治疗靶点。Trop2因在多种肿瘤细胞表面高表达得到广泛关注,单细胞表面Trop2水平几万至几十万,流行病学证明Trop2与多种肿瘤的发展和预后相关,成为抗体药物研发的靶点,Trop2抗体结合Trop2蛋白后其内吞效率很高,非常适合作为抗体偶联药物的开发。
抗体-小分子药物偶联物(Antibody-drug conjugate,ADC)是新一代抗体靶向治疗药物,主要应用于癌症肿瘤的治疗。ADC药物由小分子细胞毒性药物(Drug)、抗体(Antibody)以及连接抗体和细胞毒性药物的连接子(Linker)三部分组成,小分子细胞毒性药物通过化学偶联的方法结合到抗体蛋白上。ADC药物利用抗体特异地识别并引导小分子药物到达表达癌症特异性抗原的癌细胞靶点,并通过细胞内吞效应进入癌细胞。接头部分在胞内低pH值环境或溶酶体蛋白酶的作用下断裂,释放出小分子细胞毒性药物,从而达到特异杀死癌细胞而不损伤正常组织细胞的作用。因此,ADC药物同时结合了抗体的靶向专一性和小分子毒素对癌细胞的高毒性的特点,大大扩展了药物的有效治疗剂量窗口(Therapeutic window)。临床研究已证明,ADC药物的药效高、在血液中相对稳定,能有效地降低小分子细胞毒性药物(化药)本身对循环系统以及健康组织的毒性,是目前国际上抗癌药物的研发热点。
发明内容
本发明要解决的技术问题是克服现有的抗体药物偶联物种类单一的缺陷,而提供了一种靶向TROP2的抗体药物偶联物、其制备方法及应用。
本发明开发了的抗体药物偶联物,具有很好的靶向性,对阳性表达TROP2的肿瘤细胞具有很好的抑制效果,并且,具有很好的成药性,安全性高。该抗体药物偶联物具有TROP2的抑制效果,还对NCI-N87、MDA-MB-468和BXPC3细胞中的至少一种有良好的抑制效果。
本发明通过以下技术方案解决上述技术问题。
本发明提供了一种如式I所示的抗体药物偶联物或其药学上可接受的盐;
其中,Ab为TROP2抗体;
所述的TROP2抗体中轻链的氨基酸序列如序列表SEQ ID NO:1所示,重链的氨基酸序列如序列表SEQ ID NO:2所示;
m为2~8;
R2和R5分别独立地为H、C1-C6烷基或卤素;
R3和R6分别独立地为H、C1-C6烷基或卤素;
R4和R7分别独立地为C1-C6烷基;
R1为被一个或多个-NR1-1R1-2取代的C1~C6烷基、被一个或多个R1-3S(O)2-取代的C1~C6烷基、C1~C6烷基或C3~C10环烷基;所述的R1-1、R1-2和R1-3分别独立地为C1~C6烷基;
L1独立地为苯丙氨酸残基、丙氨酸残基、甘氨酸残基、异亮氨酸残基、亮氨酸残基、脯氨酸残基和缬氨酸残基中的一种或多种;p为2~4;
其中n独立地为1~12,c端通过羰基与L1相连,f端与所述的L3的d端相连;
在本发明一优选实施方案中,上述的抗体偶联药物里,某些基团具有如下定义,未提及的基团的定义如上任一方案所述(本段内容以下简称为“在本发明一优选实施方案中”):
在本发明一优选实施方案中,当所述的R2和R5分别独立地为C1-C6烷基时,所述的C1~C6烷基优选为C1~C4烷基,进一步优选为甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基,最优选为甲基。
在本发明一优选实施方案中,当所述的R2和R5分别独立地为卤素时,所述的卤素优选为氟、氯、溴或碘,进一步优选为氟。
在本发明一优选实施方案中,当所述的R3和R6分别独立地为C1-C6烷基时,所述的C1~C6烷基优选为C1~C4烷基,进一步优选为甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基,最优选为甲基。
在本发明一优选实施方案中,当所述的R3和R6分别独立地为卤素时,所述的卤素优选为氟、氯、溴或碘,进一步优选为氟。
在本发明一优选实施方案中,当所述的R4和R7分别独立地为C1-C6烷基时,所述的C1~C6烷基优选为C1~C4烷基,进一步优选为甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基,最优选为乙基。
在本发明一优选实施方案中,R2和R5分别独立地为C1-C6烷基。
在本发明一优选实施方案中,R3和R6分别独立地为卤素。
在本发明一优选实施方案中,R4和R7为乙基。
在本发明一优选实施方案中,当所述的R1为被一个或多个-NR1-1R1-2取代的C1~C6烷基时,所述的C1~C6烷基优选为甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基,最优选为乙基。
在本发明一优选实施方案中,当所述的R1为被多个-NR1-1R1-2取代的C1~C6烷基时,所述的多个为两个或三个。
在本发明一优选实施方案中,当所述的R1-1和R1-2各自独立地为C1~C6烷基时,所述的C1~C6烷基优选为甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基,最优选为甲基。
在本发明一优选实施方案中,当所述的R1为被一个或多个-NR1-1R1-2取代的C1~C6烷基时,所述的-NR1-1R1-2优选为-N(CH3)2。
在本发明一优选实施方案中,当所述的R1为被一个或多个R1-3S(O)2-取代的C1~C6烷基时,所述的C1~C6烷基优选为C1~C4烷基,进一步优选为甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基,最优选为乙基。
在本发明一优选实施方案中,当所述的R1为被多个R1-3S(O)2-取代的C1~C6烷基时,所述的多个为两个或三个。
在本发明一优选实施方案中,当所述的R1-3为C1~C6烷基时,所述的C1~C6烷基优选为甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基,最优选为甲基。
在本发明一优选实施方案中,当所述的R1为C1~C6烷基时,所述的C1~C6烷基优选为甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基,最优选为甲基。
在本发明一优选实施方案中,所述的m为整数(例如2、3、4、5、6、7或8)或非整数,优选为3-5,进一步优选为3.5-4.5,再进一步优选地为3.8-4.2,例如3.88、3.90、3.96、3.97、3.98、4.00、4.03、4.05、4.10、4.12或4.13。
在本发明一优选实施方案中,所述的L1优选为苯丙氨酸残基、丙氨酸残基、甘氨酸残基、异亮氨酸残基、亮氨酸残基、脯氨酸残基和缬氨酸残基中的一种或多种,更优选为苯丙氨酸残基、丙氨酸残基、甘氨酸残基和缬氨酸残基中的一种或多种,进一步优选为缬氨酸残基和/或丙氨酸残基,所述的多种优选为两种或三种,所述的p优选为2。
在本发明一优选实施方案中,所述的n优选为8~12,例如8、9、10、11和12,再例如8或12。
在本发明一优选实施方案中,当所述的R1-1、R1-2和R1-3独立地为C1~C6烷基时,所述的C1~C6烷基优选C1~C4烷基,进一步优选为甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基,最优选为甲基。
在本发明一优选实施方案中,所述的R1优选为被一个或多个-NR1-1R1-2取代的C1~C6烷基、被一个或多个R1-3S(O)2-取代的C1~C6烷基、C1~C6烷基或C3~C10环烷基,更优选为被一个或多个-NR1-1R1-2取代的C1~C6烷基、被一个或多个R1-3S(O)2-取代的C1~C6烷基、或、C1~C6烷基,进一步优选为被一个或多个-NR1-1R1-2取代的C1~C6烷基、或、被一个或多个R1- 3S(O)2-取代的C1~C6烷基,最优选为被一个或多个R1-3S(O)2-取代的C1~C6烷基。
在本发明中,当Ab为TROP2抗体时,所述的TROP2抗体为TROP2抗体的残基(TROP2抗体中的一个巯基上的氢被取代形成的基团)。
在本发明一优选实施方案中,所述的如式I所示的化合物为如下任一方案:
方案一:
R2和R5分别独立地为C1-C6烷基;
R1为被一个或多个-NR1-1R1-2取代的C1~C6烷基、被一个或多个R1-3S(O)2-取代的C1~C6烷基、或、C1~C6烷基;
L1为苯丙氨酸残基、丙氨酸残基、甘氨酸残基和缬氨酸残基中的一种或多种;
方案二:
R2和R5分别独立地为C1-C6烷基;
m为3.5-4.5;
R1为被一个或多个-NR1-1R1-2取代的C1~C6烷基、被一个或多个R1-3S(O)2-取代的C1~6烷基、或、C1~C6烷基;
L1独立地为缬氨酸残基和/或丙氨酸残基;
方案三:
R1为被一个或多个-NR1-1R1-2取代的C1~C6烷基、被一个或多个R1-3S(O)2-取代的C2~C6烷基、或、C1~C6烷基;
L1独立地为缬氨酸残基和/或丙氨酸残基;
方案四:
m为3.5-4.5,
R1为被一个或多个-NR1-1R1-2取代的C1~C6烷基、被一个或多个R1-3S(O)2-取代的C1~C6烷基、或、C1~C6烷基;
L1独立地为缬氨酸残基和/或丙氨酸残基。
在本发明一优选实施方案中,所述的抗体药物偶联物优选为
在本发明一优选实施方案中,所述的Ab为TROP2抗体;D为
L1为缬氨酸残基和/或丙氨酸残基,p为2,(L1)p优选为R1为被一个或多个-NR1-1R1-2取代的C1~26烷基、被一个或多个R1-3S(O)2-取代的C1~C6烷基或C1~C6烷基,优选为被一个或多个-NR1-1R1-2取代的C1~C6烷基、或、被一个或多个R1-3S(O)2-取代的C1~C6烷基,进一步优选为被一个或多个R1-3S(O)2-取代的C1~C6烷基;所述的R1-1、R1-2和R1-3独立地为C1~C4烷基,优选为甲基;所述的被一个或多个-NR1-1R1-2取代的C1~C6烷基优选为所述的被一个或多个R1-3S(O)2-取代的C1~C6烷基优选为L2为L3为
在本发明一优选实施方案中,所述的抗体药物偶联物优选为如下所示的任一化合物:
其中,Ab为TROP2抗体,m为3.8-4.2,优选为3.88、3.90、3.96、3.97、3.98、4.00、4.03、4.05、4.10、4.12或4.13。
在本发明一优选实施方案中,所述的抗体药物偶联物优选为如下所示的任一化合物:
其中,Ab为TROP2抗体。
在本发明一优选实施方案中,所述的抗体药物偶联物优选为如下所示的任一化合物:
其中,其中,Ab为TROP2抗体,m为3.90、4.00或4.10。
本发明还提供了一种上述抗体药物偶联物的制备方法,其包括以下步骤:将如式II所示的化合物与Ab-氢进行如下所示的偶联反应即可;
其中,所述的L1、L2、L3、R1、p和Ab的定义如上所述。
本发明中,所述的偶联反应的条件和操作可为本领域该偶联反应常规的条件和操作。
本发明还提供了一种药物组合物,其包括物质X和药用辅料,所述的物质X为上述抗体药物偶联物或其药学上可接受的盐。
所述的药物组合物中,所述的上述的物质X的用量可为治疗有效量。
本发明还提供了一种上述的物质X或上述的药物组合物在制备TROP2蛋白抑制剂中的应用。本发明还提供了一种上述的物质X或上述的药物组合物在制备用于治疗和/或预防肿瘤的药物中的应用,所述的肿瘤优选TROP2阳性肿瘤。
所述的应用中,所述的TROP2阳性肿瘤优选TROP2阳性胃癌、三阴乳腺癌和人胰腺癌的一种或多种。
在本发明某些实施例中,在所述的胃癌中,胃癌细胞为NCI-N87细胞;
在本发明某些实施例中,在所述的三阴乳腺癌中,三阴乳腺癌细胞为MDA-MB-468细胞;
在本发明某些实施例中,在所述的胰腺癌中,胰腺癌细胞为BXPC3细胞。
除非另有说明,在本发明说明书和权利要求书中出现的以下术语具有下述含义:
所述的药用辅料可为药物生产领域中广泛采用的辅料。辅料主要用于提供一个安全、稳定和功能性的药物组合物,还可以提供方法,使受试者接受给药后活性成分以所期望速率溶出,或促进受试者接受组合物给药后活性成分得到有效吸收。所述的药用辅料可以是惰性填充剂,或者提供某种功能,例如稳定该组合物的整体pH值或防止组合物活性成分的降解。所述的药用辅料可包括下列辅料中的一种或多种:缓冲剂、螯合剂、防腐剂、助溶剂、稳定剂、赋形剂和表面活性剂着色剂、矫味剂和甜味剂。
天然或者天然序列的TROP2可以分离自大自然,也可以用重组DNA技术、化学合成法,或以上及类似技术的联合制得。
抗体在此取其最广义的解释,其可透过位于该免疫球蛋白分子的可变区的至少一个抗原辨认区特异性地与目标结合,诸如碳水化合物、多核苷酸、脂肪、多肽等。具体包括完整的单克隆抗体,多克隆抗体,双特异抗体以及抗体片段,只要他们具有所需的生物活性。
本发明的抗体可利用该领域广为周知的技术制备,例如杂交瘤方法、重组DNA技术、噬菌体展示技术、合成技术或该等技术的组合、或该领域己知的其它技术。
关于术语“药物抗体偶联比率”(drug-antibodyratio,即DAR)的说明。L-D是和抗体上的缀合点具反应性的基团,L是连接子,D是在连接L的抗体上进一步缀合的细胞毒剂,在本发明中D为Dxd,每个抗体最终缀合D的DAR数目用m表示或者m也可表示单个抗体缀合D的数量。在一些实施方式中,m实际上为介于2至8、3至7或3至5的平均值,或m为2、3、4、5、6、7或8中的某个整数;在一些实施方式中,m为3.5-4.5的平均值(例如3.88、3.90、3.96、3.97、3.98、4.00、4.03、4.05、4.10、4.12或4.13);在其它实施方式中,m为2、3、4、5、6、7或8的平均值。
连接子是指抗体与药物间的直接或间接连接。将连接子连接至mAb可经由许多方式完成,诸如经由表面赖氨酸、还原偶合至经氧化的碳水化合物、及经由还原链间二硫键所释放的半胱氨酸残基。多种ADC连接系统是该领域所知,包括以腙、双硫及肽为基底的连接。
术语“药学上可接受的盐”是指本发明化合物与相对无毒的、药学上可接受的酸或碱制备得到的盐。当本发明的化合物中含有相对酸性的功能团时,可以通过在纯的溶液或合适的惰性溶剂中用足够量的药学上可接受的碱与这类化合物的中性形式接触的方式获得碱加成盐。药学上可接受的碱加成盐包括但不限于:锂盐、钠盐、钾盐、钙盐、铝盐、镁盐、锌盐、铋盐、铵盐、二乙醇胺盐。当本发明的化合物中含有相对碱性的官能团时,可以通过在纯的溶液或合适的惰性溶剂中用足够量的药学上可接受的酸与这类化合物的中性形式接触的方式获得酸加成盐。所述的药学上可接受的酸包括无机酸,所述无机酸包括但不限于:盐酸、氢溴酸、氢碘酸、硝酸、碳酸、磷酸、亚磷酸、硫酸等。所述的药学上可接受的酸包括有机酸,所述有机酸包括但不限于:乙酸、丙酸、草酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、水杨酸、酒石酸、甲磺酸、异烟酸、酸式柠檬酸、油酸、单宁酸、泛酸、酒石酸氢、抗坏血酸、龙胆酸、富马酸、葡糖酸、糖酸、甲酸、乙磺酸、双羟萘酸(即4,4’-亚甲基-双(3-羟基-2-萘甲酸))、氨基酸(例如谷氨酸、精氨酸)等。当本发明的化合物中含有相对酸性和相对碱性的官能团时,可以被转换成碱加成盐或酸加成盐。具体可参见Berge et al.,″Pharmaceutical Salts″,Journal of Pharmaceutical Science 66:1-19(1977)、或、Handbook of PharmaceuticalSalts:Properties,Selection,and Use(P.Heinrich Stahl and Camille G.Wermuth,ed.,Wiley-VCH,2002)。
术语“治疗”或它的同等表达当用于例如癌症时,指用来减少或消除患者体内癌细胞数目或减轻癌症的症状的程序或过程。癌症或另外的增生性障碍的“治疗”不一定指癌症细胞或其它障碍会实际上被消除,细胞或障碍的数目会实际上被减少或者癌症或其它障碍的症状会实际上被减轻。通常,即使只具有低的成功可能性也会进行治疗癌症的方法,但是考虑到患者的病史和估计的生存预期,其仍然被认为诱导总体有益的作用过程。
术语“预防”是指获得或发生疾病或障碍的风险降低。
术语“环烷基”是指具有三到二十个碳原子的饱和的环烃原子团(例如C3-C6环烷基),包括单环环烷基和多环环烷基。环烷基包含3至20个碳原子,优选包含3至10个碳原子,更优选包含3至6个碳原子。环烷基的实例包括但不仅限于环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环壬基和环癸基。
术语“烷基”是指具有指定的碳原子数的直链或支链烷基。烷基的实例包括甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基、仲丁基、正戊基、异戊基、正己基、正庚基、正辛基及其类似烷基。
术语“卤素”是指氟、氯、溴或碘。
在不违背本领域常识的基础上,上述各优选条件,可任意组合,即得本发明各较佳实例。
如无特殊说明,本发明中的室温是指20-30℃。
本发明所用试剂和原料均市售可得。
本发明的积极进步效果在于:
1.本发明提供的包含有TROP2抗体的抗体药物偶联物,具有很好的靶向性,对表达TROP2等的多种肿瘤细胞具有很好的抑制效果。
2.体内研究表明,本发明的抗体药物偶联物具有更佳的体外细胞毒性、体内抗肿瘤活性。
3.本发明的抗体药物偶联物溶解性好,具有很好的成药性,偶联制备过程无沉淀等异常现象发生,非常利于抗体药物偶联物的制备。
附图说明
图1为FDA018抗体的轻、重链表达载体构建,其中Ab-L为抗体的轻链,Ab-H为抗体的重链。
具体实施方式
下面通过实施例的方式进一步说明本发明,但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法,按照常规方法和条件,或按照商品说明书选择。
缩写说明:
PCR 聚合酶链反应
CHO 中国仓鼠卵巢细胞
HTRF 均相时间分辨荧光
PB 磷酸缓冲液
EDTA 乙二胺四乙酸
TECP 三(2-羧乙基)膦
DMSO 二甲基亚砜
DMF N,N-二甲基甲酰胺
His 组氨酸
HATU 2-(7-氧化苯并三氮唑)-N,N,N′,N′-四甲基脲六氟磷酸盐
v/v V/V,体积比
UV 紫外可见光
ELISA 酶联免疫吸附试验
BSA 牛血清白蛋白
rpm 转/每分钟
FBS 胎牛血清
实施例1:TROP2抗体的制备
本发明中选取高亲和力并特异性靶向TROP2的单克隆抗体FDA018,其轻链的氨基酸序列如SEQ ID NO:1所示,其重链的氨基酸序列如SEQ ID NO:2所示。FDA018其轻重链核苷酸序列通过全基因合成(苏州金唯智)方式获得。通过EcoRI和HindIII(购于TAKARA)双酶切分别单独构建至pV81载体中(如图1),通过连接转化至Trans 1-T1感受态细胞(购自北京全式金生物,货号:CD501-03)中,从中挑取克隆进行PCR鉴定并送检、测序确认,培养扩增阳性克隆进行质粒中抽,从而获得抗体轻链真核表达质粒FDA018-L/pV81和抗体重链真核表达质粒FDA018-H/pV81,对这两个质粒使用XbaI(购自Takara,货号:1093S)进行酶切线性化,轻、重链真核表达质粒比例1.5/1,通过电击转化至已适应悬浮生长的CHO细胞中(购于ATCC),将电击后细胞以2000-5000细胞/孔接至96孔板中,培养3周后使用HTRF法(均相时间分辨荧光)测定表达量,从中挑选表达量前十的细胞池扩增后冻存。复苏一支细胞至125ml摇瓶中(培养体积30ml),37℃,5.0%CO2,130rpm震荡培养,3天后扩至1000ml摇瓶中(培养体积300ml),37℃,5.0%CO2,130rpm震荡培养,第四天开始隔天补加起始培养体积5-8%的补料培养基,培养至10-12天结束培养,收获液9500rpm离心15min,去除细胞沉淀,收集上清液,再用0.22μm滤膜过滤处理,处理好的样品使用MabSelect亲和层析柱(购于GE公司)进行纯化得到抗体FDA018。
FDA018轻链的氨基酸序列如下所示:
SEQ ID NO:1:
FDA018重链的氨基酸序列如下所示:
SEQ ID NO:2:
实施例2:连接基-药物偶联物的合成
实施例2-1:LE12的合成
中间体2的合成:
将(S)-2-叠氮丙酸(10g,86.9mmol)与4-氨基苄醇(21.40g,173.8mmol)溶于300mL二氯甲烷和甲醇混合溶剂中(体积比2∶1),加入2-乙氧基-1-乙氧碳酰基-1,2-二氢喹啉(21.49g,86.9mmol),室温反应5小时后,减压蒸干溶剂,然后,所得粗品用硅胶柱层析[二氯甲烷∶乙酸乙酯=1∶1(v/v)]纯化得到中间体2(16.3g,收率85%),ESI-MS m/z:221(M+H)。
中间体3的合成:
将中间体2(15g,68.2mmol)与二(对硝基苯)碳酸酯(22.82g,75.02mmol)混合溶于200mL无水N,N-二甲基甲酰胺中,加入25mL三乙胺,室温反应2小时。通过液质联用色谱监测原料反应完毕后,加入甲胺盐酸盐(6.91g,102.3mmol),继续室温反应1小时。反应完毕减压蒸馏去除大部分溶剂,然后加入200mL水,200mL乙酸乙酯,分液后收集有机相,有机相经干燥后浓缩,所得粗品经过硅胶柱层析[二氯甲烷∶乙酸乙酯=10∶1(v/v)]纯化得到中间体3(18.9g,收率100%),ESI-MS m/z:278(M+H)。
中间体5的合成:
将中间体3(10g,36.1mmol)与多聚甲醛(1.63g,54.2mmol)混合溶于150mL无水二氯甲烷中,慢慢加入三甲基氯硅烷(6.28g,57.76mmol),室温反应2小时得到中间体4的粗品溶液,通过取样加甲醇淬灭后液质联用监测反应,待反应完毕将反应液过滤然后向滤液中加入羟基乙酸叔丁酯(9.54g,72.2mmol)和三乙胺(10mL,72.2mmol),继续室温反应2小时。反应完毕减压蒸馏去除大部分溶剂,所得粗品经过硅胶柱层析[石油醚∶乙酸乙酯=3∶1(v/v)]纯化得到中间体5(11.2g,收率74%),ESI-MS m/z:422(M+H)。
中间体6的合成:
将中间体5(10g,23.8mmol)溶于80mL无水四氢呋喃中,加入80mL水,然后加入三(2-羧乙基膦)盐酸盐(13.6g,47.6mmol),室温反应4小时。反应完毕减压蒸馏去除四氢呋喃,然后加乙酸乙酯萃取,所得有机相经干燥后减压蒸除溶剂,经硅胶柱层析[二氯甲烷∶甲醇=10∶1(v/v)]纯化得到中间体6(8.1g,收率86%),ESI-MS m/z:396(M+H)。
中间体8的合成:
将的中间体6(5g,12.7mmol)溶于60mL二氯甲烷和甲醇混合溶剂中(v/v=2∶1)中,慢慢加入三氟乙酸3mL,室温反应30分钟。反应完毕加等体积水和乙酸乙酯,有机相干燥后浓缩,所得粗品直接用于下一步。
将上述步所获得的粗品溶于50mL无水N,N-二甲基甲酰胺中,加入Fmoc-缬氨酸羟基琥珀酰亚胺酯(8.3g,19.1mmol),三乙胺(5mL),室温反应2小时。反应完毕,减压蒸馏去除大部分溶剂,所得粗品经硅胶柱层析[二氯甲烷∶甲醇=10∶1(v/v)]纯化得到中间体8(5.4g,收率64%),ESI-MSm/z:661(M+H)。
中间体9的合成:
将中间体8(1g,1.5mmol)与Exatecan甲磺酸盐(0.568g,1mmol)混合于30mL无水N,N-二甲基甲酰胺中,加入2-(7-氧化苯并三氮唑)-N,N,N′,N′-四甲基脲六氟磷酸盐(1.14g,3.0mmol),三乙胺2mL,室温反应2h。反应完毕,减压蒸馏去除溶剂,所得粗品经硅胶柱层析[氯仿∶甲醇=10∶1(v/v)]纯化得到中间体9(0.94g,收率87%),ESI-MS m/z:1078(M+H)。
化合物LE12的合成:
将中间体9(1g,0.929mmol)溶于20mL无水DMF中,加入0.5mL 1,8-二氮杂二环十一碳-7-烯,室温反应1小时。待原料反应完毕,直接加入6-(马来酰亚胺基)己酸琥珀酰亚胺酯(428.5mg,1.39mmol),室温搅拌1小时。减压馏去溶剂,所得粗品经硅胶柱层析[氯仿∶甲醇=8∶1(v/v)]纯化得到标题化合物(0.7g,收率73%),ESI-MS m/z:1035(M+H)。
实施例2-2:化合物LE13的合成
中间体14的合成
将市售的中间体12(267mg,0.8mmol)与多聚甲醛(50mg,1.6mmol)混合溶于20mL无水二氯甲烷中,慢慢加入三甲基氯硅烷(0.3mL,3.4mmol),加料完毕后室温反应2小时。然后通过取样加甲醇淬灭后液质联用监测反应,待反应完毕后将反应液过滤,然后向滤液中加入羟基乙酸叔丁酯(211mg,1.6mmol)和潘必啶0.5mL,继续室温反应约2小时,反应完后减压蒸馏去除大部分溶剂,所得粗品经过硅胶柱层析[二氯甲烷∶甲醇=20∶1(v/v)]纯化得到中间体14(260mg,收率68%),ESI-MS m/z:479(M+H)。
中间体15的合成
将中间体14(238mg,0.50mmol)溶于6mL二氯甲烷和甲醇混合溶剂中(v/v=2∶1)中,慢慢加入三氟乙酸0.3mL,室温反应30分钟。反应完毕加等体积水和乙酸乙酯,有机相干燥后浓缩,所得粗品直接用于下一步。
中间体16的合成
将上述步骤所获得的粗品与Exatecan甲磺酸盐(170mg,0.30mmol)混合于5mL无水N,N-二甲基甲酰胺中,加入2-(7-氧化苯并三氮唑)-N,N,N′,N′-四甲基脲六氟磷酸盐(341mg,0.90mmol),三乙胺0.60mL,室温反应2h。反应完毕,减压蒸馏去除溶剂,所得粗品经硅胶柱层析[氯仿∶甲醇=10∶1(v/v)]纯化得到中间体16(210mg,83%),ESI-MS m/z:840(M+H)。
中间体17的合成
将中间体16(100mg,0.12mmol)溶于15mL无水四氢呋喃中,加入3mL水,然后加入1摩尔/升的三乙基膦水溶液0.3mL,室温反应4小时。监测反应完毕后将反应液减压蒸馏去除四氢呋喃,向所余水溶液中加碳酸氢钠调节pH至中性,然后加二氯甲烷萃取,所得有机相干燥后减压蒸除溶剂,所得粗品经硅胶柱层析[二氯甲烷∶甲醇=10∶1(v/v)]纯化得到中间体17(69mg,收率71%),ESI-MS m/z:814(M+H)。
化合物LE13的合成
按照上步合成方法得到的中间体17(120mg,0.15mmol)与市售的原料MC-V(102mg,0.33mmol)混合于40mL二氯甲烷中,加入缩合剂2-乙氧基-1-乙氧碳酰基-1,2-二氢喹啉(82mg,0.33mmol),室温反应过夜,反应完毕减压蒸干溶剂,所得粗品经硅胶柱层析[二氯甲烷∶甲醇=10∶1(v/v)]纯化得到化合物LE13(116mg,收率70%),ESI-MS m/z:1106.5(M+H)。
实施例2-3:化合物LE14的合成
中间体19的合成
将市售的中间体18(300mg,0.8mmol)与多聚甲醛(50mg,1.6mmol)混合溶于20mL无水二氯甲烷中,慢慢加入三甲基氯硅烷(0.3mL,3.4mmol),室温反应2小时,通过取样加甲醇淬灭后液质联用监测反应。待反应完毕将反应液过滤,然后向滤液中加入羟基乙酸叔丁酯(211mg,1.6mmol)和三乙胺(0.22m,1.6mmol),继续室温反应约2小时,反应完后减压蒸馏去除大部分溶剂,所得粗品经过硅胶柱层析[二氯甲烷∶甲醇=20∶1(v/v)]纯化得到中间体19(349mg,收率85%),ESI-MSm/z:514(M+H),1H NMR(400MHz,CDCl3)δ8.13(s,1H),7.56(d,J=7.5Hz,2H),7.35(s,2H),5.14(s,2H),4.91(s,2H),4.25(q,J=7.1Hz,1H),3.99(d,J=42.5Hz,2H),3.85(t,J=6.2Hz,2H),3.40(dd,J=18.5,7.6Hz,2H),2.89(d,J=48.6Hz,3H),1.65(d,J=6.8Hz,3H),1.46(s,9H)。
中间体20的合成
将中间体19(257mg,0.50mmol)溶于6mL二氯甲烷和甲醇混合溶剂中(v/v=2∶1)中,慢慢加入三氟乙酸0.3mL,室温反应30分钟。反应完毕加等体积水和乙酸乙酯,有机相干燥后浓缩,所得粗品直接用于下一步。
将所得粗品与Exatecan甲磺酸盐(170mg,0.30mmol)混合于5mL无水N,N-二甲基甲酰胺中,加入2-(7-氧化苯并三氮唑)-N,N,N′,N′-四甲基脲六氟磷酸盐(341mg,0.90mmol),三乙胺0.60mL,室温反应2h。反应完毕,减压蒸馏去除溶剂,所得粗品经过硅胶柱层析[二氯甲烷∶甲醇=20∶1(v/v)]纯化得到中间体20(212mg,收率81%),ESI-MS m/z:875(M+H)。1HNMR(400MHz,CDCl3)δ8.27(d,J=34.7Hz,1H),7.63-7.35(m,5H),7.21-7.10(m,1H),5.71-5.48(m,2H),5.24-4.95(m,3H),4.95-4.72(m,4H),4.45(s,1H),4.33-3.97(m,3H),3.75(s,2H),3.39-2.99(m,4H),2.76(d,J=15.3Hz,3H),2.43-2.15(m,5H),2.04(s,iH),1.94-1.75(m,2H),1.62(d,J=6.6Hz,3H),1.11-0.89(m,3H)。
中间体21的合成
将中间体20(77mg,0.09mmol)溶于12mL无水四氢呋喃中,加入3mL水,然后加入1摩尔/升的三乙基膦水溶液0.3mL,室温反应4小时。反应完毕减压蒸馏去除四氢呋喃,向所余水溶液中加碳酸氢钠调节pH至中性,然后加二氯甲烷萃取,所得有机相干燥后减压蒸除溶剂,所得粗品经硅胶柱层析[二氯甲烷∶甲醇=10∶1(v/v)]纯化得到中间体21(53mg,收率69%),ESI-MS m/z:849(M+H)。1H NMR(400MHz,DMSO)δ8.52(s,1H),7.79(d,J=10.8Hz,1H),7.67-7.55(m,2H),7.47-7.21(m,3H),6.51(s,1H),5.60(s,1H),5.52-5.32(m,2H),5.30-5.11(m,2H),5.11-4.94(m,2H),4.94-4.74(m,2H),4.02(s,2H),3.81-3.66(m,2H),3.60-3.35(m,4H),3.24-3.08(m,2H),2.94(d,J=30.8Hz,3H),2.39(s,3H),2.28-2.04(m,2H),2.00-1.73(m,2H),1.22(d,J=6.6Hz,3H),0.96-0.70(m,3H)。
化合物LE14的合成
中间体21(134mg,0.16mmol)与市售的原料MC-V(102mg,0.33mmol)混合于40mL二氯甲烷中,加入缩合剂2-乙氧基-1-乙氧碳酰基-1,2-二氢喹啉(82mg,0.33mmol),室温反应过夜,反应完毕减压蒸干溶剂,所得粗品经硅胶柱层析[二氯甲烷∶甲醇=10∶1(v/v)]纯化得到化合物LE14(137mg,收率75%),ESI-MS m/z:1141.4(M+H)。1H NMR(400MHz,DMSO)δ9.97(s,1H),8.52(s,1H),8.27-8.09(m,1H),7.88-7.70(m,2H),7.63-7.51(m,2H),7.28(s,3H),6.99(s,2H),6.51(s,1H),5.59(s,1H),5.50-5.32(m,2H),5.17(s,2H),4.98(s,2H),4.85(d,J=17.3Hz,2H),4.43-4.33(m,1H),4.21-4.12(m,1H),4.03(s,2H),3.74-3.64(m,2H),3.20-3.03(m,3H),3.02-2.84(m,4H),2.36(s,3H),2.23-2.09(m,4H),2.01-1.90(m,1H),1.90-1.78(m,2H),1.55-1.39(m,4H),1.30(d,J=6.7Hz,3H),1.23-1.11(m,2H),0.93-0.77(m,9H)。
实施例2-4:化合物LE15-LE20的合成
中间体VI可以以Fmoc-L-缬氨酸-L-丙氨酸为起始原料,参照实施例2-1中中间体3的合成方法中的步骤a和b,将其中步骤b中的甲胺盐酸盐替换为相应的市售可得的氨基化合物制备而得。后续步骤从中间体VI出发,按照与实施例2-1中的步骤c、d、f和h相同的方法,得到与中间体9相似的中间体IX,然后按照实施例6中的步骤i和j相同的步骤处理,脱除氨基保护基,然后与市售可得的不同马来酰亚胺缩合得到终产物。所用氨基化合物及马来酰亚胺结构见表1。化合物LE15:灰白色固体,ESI-MS m/z:1121.2(M+H);化合物LE16:淡黄色固体,ESI-MS m/z:1167.1(M+H);化合物LE17:黄色固体,ESI-MS m/z:1132.3(M+H);化合物LE18:淡黄色固体,ESI-MS m/z:1305.4(M+H);化合物LE19:淡黄色固体,ESI-MS m/z:1307.4(M+H);化合物LE20:淡黄色固体,ESI-MS m/z:1337.6(M+H)。
表1.合成LE15-LE20所用的中间体
实施例2-5:化合物LE21与LE22的合成
化合物DXD-1的合成
市售的Exatecan甲磺酸盐(0.568g,1mmol)与市售的2-(叔丁基二甲基硅氧)乙酸(CAS:105459-05-0,0.38g,2mmol)混合溶于20mL无水二氯甲烷中,加入缩合剂HATU(0.76g,2mmol)和1mL吡啶,室温搅拌2小时。待反应完毕后,减压蒸干溶剂,所得粗品经柱层析[二氯甲烷∶甲醇=50∶1(v/v)]纯化得到标题化合物DXD-1(0.55g,收率90%),ESI-MS m/z:608.1(M+H)。1H NMR(400MHz,CDCl3)δ7.73(d,J=10.5Hz,1H),7.64(s,1H),7.05(d,J=9.2Hz,1H),5.80-5.62(m,2H),5.41-5.14(m,4H),4.29-4.15(m,2H),4.08-4.03(m,1H),3.27-3.07(m,2H),2.45(s,3H),2.38-2.28(m,2H),1.96-1.81(m,2H),1.04(t,J=7.4Hz,3H),0.80(s,9H),0.11(s,3H),0.03(s,3H).
中间体V的制备
中间体V可以参照实施例2-1中化合物4的制备方法,将其中步骤b中的甲胺盐酸盐替换为相应的市售可得的氨基化合物制备而得。
LE21-LE22的合成
中间体V与DXD-1反应,后续经过10%三氟乙酸/二氯甲烷溶液处理得到中间体X,然后中间体X参照实施例2-1中化合物5的后续步骤e、g、i和j进行反应:中间体X经过还原得到氨基化合物,所得氨基化合物和Fmoc-缬氨酸羟基琥珀酰亚胺酯缩合,然后脱去所得产物中氨基的Fmoc保护基,所得氨基产物再和6-(马来酰亚胺基)己酸琥珀酰亚胺酯反应得到最终产物。化合物LE21:黄色固体,ESI-MS m/z:1141.2(M+H);化合物LE22:黄色固体,ESI-MSm/z:1106.6(M+H)。
实施例2-6:化合物LS13的合成
参照实施例2-4中LE15的合成方法,SN-38(7-乙基-10-羟基喜树碱)与中间体VII(R1为甲砜乙基)反应后,经脱保护,缩合等步骤得到化合物LS13:1H NMR(400MHz,DMSO)δ9.92(d,J=22.4Hz,1H),8.14(s,1H),8.08(d,J=9.1Hz,1H),7.81(d,J=8.0Hz,1H),7.70-7.50(m,3H),7.47(d,J=7.2Hz,1H),7.34(d,J=7.2Hz,1H),7.27(s,1H),7.20(s,1H),6.98(s,2H),6.51(s,1H),5.61(s,2H),5.48-5.35(m,2H),5.27(s,2H),5.10(d,J=20.6Hz,2H),4.36(s,1H),4.21-4.07(m,1H),3.84(s,2H),3.48(s,2H),3.21-2.92(m,6H),2.25-2.04(m,2H),2.04-1.78(m,3H),1.55-1.36(m,4H),1.36-1.10(m,9H),0.95-0.71(m,10H)。
实施例2-7:化合物GGFG-Dxd的合成
化合物GGFG-Dxd参照WO2015146132A1报道的已知的合成方法制备而得。ESI-MSm/z:1034.5(M+H),1H-NMR(400MHz,DMSO-d6)δ8.61(t,J=6.4Hz,1H),8.50(d,J=8.5Hz,1H),8.28(t,J=5.1Hz,1H),8.11(d,J=7.5Hz,1H),8.05(t,J=5.7Hz,1H),7.99(t,J=5.9Hz,1H),7.77(d,J=11.0Hz,1H),7.31(s,1H),7.25-7.16(m,5H),6.98(s,2H),6.51(s,1H),5.59(dt,J=7.4,4.1Hz,1H),5.41(s,2H),5.20(s,2H),4.64(d,J=6.1Hz,2H),4.53-4.40(m,1H),4.02(s,2H),3.74-3.37(m,8H),3.18-3.00(m,2H),3.04-2.97(m,1H),2.77(dd,J=13.5,9.4Hz,1H),2.38(s,3H),2.19(dd,J=14.9,8.5Hz,2H),2.11-2.05(m,2H),1.86(dd,J=14.0,6.7Hz,2H),1.45(s,4H),1.20-1.14(m,2H),0.87(t,J=7.1Hz,3H).
实施例3:抗体药物偶联物的制备
将按照实施例1方法制备得到的TROP2的抗体FDA018使用G25脱盐柱将其置换至50mM PB/1.0mMEDTA缓冲液中(pH7.0),加入5当量TECP,于25℃搅拌1小时,以使抗体链间二硫键部分打开,随后使用枸橼酸将还原后的抗体溶液pH调至5.0,使用G25脱盐柱将样品置换至20mM枸橼酸盐缓冲液,1mMEDTA缓冲液中(pH 5.0),保持水浴温度25℃,以备偶联反应。将按照上述实施例2方法制备得到的连接基-药物偶联物LE12-LE22、LS13和GGFG-Dxd分别用DMSO溶解,从中吸取4.5当量连接基-药物偶联物逐滴加至还原后的抗体溶液中,并补加DMSO至其终浓度为5%(v/v),25℃搅拌反应0.5个小时,反应完成后,使用0.22um膜过滤样品。使用切向流超滤系统纯化去除未偶联小分子,缓冲液为25mM His,6%蔗糖溶液(pH6.0),纯化后放置于-20℃冰箱中保存。使用UV法分别在280nm和370nm下测定其吸光度值,计算DAR值,结果见下表2。
按照与本实施例以上同样的操作步骤进行偶联反应,样品均按照最高DAR制备(即过量偶联),观察各偶联反应发生时沉淀的产生情况,并计算各偶联反应完成后的聚体比例和回收率,所得结果同样见表2。
表2制备不同抗体药物偶联物(ADC)的偶联情况
“/”表示未计算回收率
在本发明的抗体欧联药物的制备规程中未产生沉淀,且聚体比例在正常范围,表明本发明提供的抗体偶联药物具有很好的理化性质。
效果实施例1:抗体药物偶联物的体外杀伤活性评价
选择NCI-N87(ATCC)细胞作为实验体外活性检测用细胞株,每孔2000个细胞接种于96孔细胞培养板中,培养20-24小时。将按照实施例3方法制备的抗体药物偶联物使用含10%FBS的L15细胞培养基配制成1000、166.7、55.6、18.6、6.17、2.06、0.69、0.23、0.08、0.008和0nM共11个浓度梯度的供试品溶液,取稀释好的供试品溶液100μL/孔加入到接种细胞的培养板内,置于37℃,5%CO2培养箱培养144小时后加入LuminescentCell Viability Assay Reagent(50μL/孔),500rpm室温振荡10分钟混匀,SpectraMaxL酶标仪读取数据(OD570nm,2s间隔读数)后计算IC50结果见表3。
利用上述同样的方法,分别测试各抗体药物偶联物对购自ATCC的MDA-MB-468、和BXPC3肿瘤细胞的细胞毒杀伤活性,结果如表3所示。从表3的结果可以看出,本发明提供的抗体药物偶联物对NCI-N87、MDA-MB-468、和BXPC3等细胞都具有极佳的体外杀伤活性。而对Calu-6阴性细胞不具有杀伤活性,表明所制备的ADC具有特异性的靶向杀伤活性。
表3.抗体药物偶联物的体外杀伤活性
效果实施例2:体外血浆稳定性试验
本实施例评价按照实施例3方法制得的抗体偶联药物在人血浆中的稳定性。具体而言,在本实施例中,将实施例3的抗体偶联药物加入人血浆中,37℃水浴中放置1、3、7、14、21、28天加内标(依喜替康作为内标物质)并进行萃取然后通过高效液相色谱法检测游离药物的释放量,结果如表4所示。
表4.不同ADC在人血浆中的稳定性评价
血浆稳定性结果表明采用新技术方案得到的ADC稳定性不劣于FDA018-GGFG-DXD,而且部分更优,同时上述活性测试结果也证明部分新获得的ADC活性优于FDA018-GGFG-DXD。
效果实施例3:连接基-药物偶联物的体外酶切实验
连接基-药物偶联物(LE14和GGFG-Dxd)与组织蛋白酶B在三个不同pH(5.0,6.0,7.0)缓冲液中共孵育,不同时间点取样进入高效液相色谱-质谱联用仪,外标法(以DXD为外标)确定药物的释放百分比。实验结果(如表5所示)表明GGFG-Dxd在所用的pH范围内酶切速度较慢,而本发明的LE14在pH 5.0至pH 7.0的范围内都能快速的酶切。
表5.LE14和GGFG-Dxd体外在不同pH的酶切情况
效果实施例4:FDA018-LS13的体外酶切实验
选择NCI-N87细胞株作为实验细胞株,样品在组织蛋白酶B体系(100mM醋酸钠-醋酸缓冲液,4mM二硫苏糖醇,pH 5.0)中37℃孵育4小时后,所得样品用培养基稀释至不同浓度,按照SN-38浓度70nM-0.003nM设定8个浓度(1.5-10倍稀释),观察144小时对细胞株的杀伤(抑制)能力变化,并通过Luminescent Cell Viability Assay化学发光染色,读取荧光数据后计算IC50数值。
将以上在组织蛋白酶B体系中37℃孵育4小时所得的酶切样品经过适量乙醇沉淀去除蛋白,通过高效液相色谱检测释放产生的小分子化合物,并以等量SN-38作为参比,测定4小时释放率,结果显示释放率达到99%。
实验结果(如表6所示)显示,FDA018-LS13经过酶切处理后细胞毒活性与等当量的SN-38几乎相同,也表明FDA018-LS13在组织蛋白酶B作用下几乎完全释放出了SN-38并发挥作用,而FDA018-LS13内吞进入溶酶体则可能发生了不可预知的变化导致SN-38不能有效发挥作用。
表6.FDA018-LS13被组织蛋白酶B体系酶切前后对NCI-N87细胞株的杀伤活性变化
效果实施例5:测试FDA018-LE14在NCI-N87人胃癌模型中的抗肿瘤活性
选择6-8周大的雌性Balb/c nude小鼠右侧颈背部皮下注射溶于100ul PBS溶液的5×106人胃癌细胞(NCI-N87),待肿瘤生长至平均体积150-200mm3时,根据肿瘤大小和小鼠体重随机分成5组,每组6只动物,分别为空白对照组、以及抗体药物偶联物FDA018-GGFG-DXD和FDA018-LE14各分别两个剂量组,具体地,01组为空白对照组;02组为4.0mg/kg的FDA018-GGFG-DXD组;03组为2.0mg/kg的FDA018-GGFG-DXD组;04组为4.0mg/kg的FDA018-LE14组;05组为2.0mg/kg的FDA018-LE14组;腹腔给药,每周给药一次。每周两次测量实验动物体重和肿瘤体积并观察实验过程中动物生存状态。结果如表7所示,空白对照组小鼠在结束给药后时平均肿瘤体积为1388.47mm3。测试药2.0mg/kg的FDA018-GGFG-DXD治疗组在结束给药后第14天平均肿瘤体积为1235.21mm3,4.0mg/kg的FDA018-GGFG-DXD治疗组在结束给药后第14天平均肿瘤体积为721.09mm3。测试药2.0mg/kg的FDA018-LE14治疗组在结束给药后第14天平均肿瘤体积为1342.31mm3,4.0mg/kg的FDA018-LE14治疗组在结束给药后第14天平均肿瘤体积为435.36mm3。实验结果显示FDA018-LE14具有较好的体内抗肿瘤活性,同时所有实验小鼠无死亡情况,无体重减轻情况,表明FDA018-LE14具有很好的安全性。
表7.FDA018-LE14在NCI-N87人胃癌模型中模型中的抗肿瘤活性
SEQUENCE LISTING
<110> 上海复旦张江生物医药股份有限公司
<120> 一种靶向TROP2的抗体药物偶联物、其中间体、制备方法及应用
<130> P20017417C
<160> 2
<170> PatentIn version 3.5
<210> 1
<211> 214
<212> PRT
<213> Homo sapiens
<400> 1
Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asp Val Ser Ile Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Tyr Arg Tyr Thr Gly Val Pro Asp Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln His Tyr Ile Thr Pro Leu
85 90 95
Thr Phe Gly Ala Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 2
<211> 451
<212> PRT
<213> Homo sapiens
<400> 2
Gln Val Gln Leu Gln Gln Ser Gly Ser Glu Leu Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Gly Met Asn Trp Val Lys Gln Ala Pro Gly Gln Gly Leu Lys Trp Met
35 40 45
Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Thr Asp Asp Phe
50 55 60
Lys Gly Arg Phe Ala Phe Ser Leu Asp Thr Ser Val Ser Thr Ala Tyr
65 70 75 80
Leu Gln Ile Ser Ser Leu Lys Ala Asp Asp Thr Ala Val Tyr Phe Cys
85 90 95
Ala Arg Gly Gly Phe Gly Ser Ser Tyr Trp Tyr Phe Asp Val Trp Gly
100 105 110
Gln Gly Ser Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
225 230 235 240
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
355 360 365
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly Lys
450
Claims (11)
1.一种如式I所示的抗体药物偶联物或其药学上可接受的盐;
其中,Ab为TROP2抗体;
所述的TROP2抗体中轻链的氨基酸序列如序列表SEQ ID NO:1所示,重链的氨基酸序列如序列表SEQ ID NO:2所示;
m为2~8;
R2和R5分别独立地为H、C1-C6烷基或卤素;
R3和R6分别独立地为H、C1-C6烷基或卤素;
R4和R7分别独立地为C1-C6烷基;
R1为被一个或多个-NR1-1R1-2取代的C1~C6烷基、被一个或多个R1-3S(O)2-取代的C1~C6烷基、C1~C6烷基或C3~C10环烷基;所述的R1-1、R1-2和R1-3分别独立地为C1~C6烷基;
L1独立地为苯丙氨酸残基、丙氨酸残基、甘氨酸残基、异亮氨酸残基、亮氨酸残基、脯氨酸残基和缬氨酸残基中的一种或多种;p为2~4;
其中n独立地为1~12,c端通过羰基与L1相连,f端与所述的L3的d端相连;
2.如权利要求1所述的抗体药物偶联物或其药学上可接受的盐,其特征在于:
所述的L3的b端与所述的抗体上的巯基以硫醚的形式相连;
和/或,当所述的R2和R5分别独立地为C1-C6烷基时,所述的C1~C6烷基为C1~C4烷基;
和/或,当所述的R2和R5分别独立地为卤素时,所述的卤素为氟、氯、溴或碘;
和/或,当所述的R3和R6分别独立地为C1-C6烷基时,所述的C1~C6烷基为C1~C4烷基;
和/或,当所述的R3和R6分别独立地为卤素时,所述的卤素为氟、氯、溴或碘;
和/或,当所述的R4和R7分别独立地为C1-C6烷基时,所述的C1~C6烷基为C1~C4烷基;
和/或,当所述的R1为被一个或多个-NR1-1R1-2取代的C1~C6烷基时,所述的C1~C6烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基,优选为乙基;
和/或,当所述的R1为被多个-NR1-1R1-2取代的C1~C6烷基时,所述的多个为两个或三个;
和/或,当所述的R1-1和R1-2各自独立地为C1~C6烷基时,所述的C1~C6烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基,优选为甲基;
和/或,当所述的R1为被一个或多个R1-3S(O)2-取代的C1~C6烷基时,所述的C1~C6烷基为C1~C4烷基,优选为甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基,最优选为乙基;
和/或,当所述的R1为被多个R1-3S(O)2-取代的C1~C6烷基时,所述的多个为两个或三个;
和/或,当所述的R1-3为C1~C6烷基时,所述的C1~C6烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基,优选为甲基;
和/或,当所述的R1为C1~C6烷基时,所述的C1~C6烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基,优选为甲基;
和/或,所述的m为整数或非整数,优选为3-5,进一步优选为3.5-4.5;
和/或,所述的n为8~12;
和/或,p为2;
和/或,当所述的R1-1、R1-2和R1-3独立地为C1~C6烷基时,所述的C1~C6烷基为C1~C4烷基,优选为甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基,最优选为甲基。
3.如权利要求2所述的抗体药物偶联物或其药学上可接受的盐,其特征在于:
当所述的R2和R5分别独立地为C1-C6烷基时,所述的C1~C6烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基,优选为甲基;
和/或,当所述的R2和R5分别独立地为卤素时,所述的卤素为氟;
和/或,当所述的R3和R6分别独立地为C1-C6烷基时,所述的C1~C6烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基,优选为甲基;
和/或,当所述的R3和R6分别独立地为卤素时,所述的卤素为氟;
和/或,当所述的R4和R7分别独立地为C1-C6烷基时,所述的C1~C6烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基,优选为乙基;
和/或,当所述的R1为被一个或多个-NR1-1R1-2取代的C1~C6烷基时,所述的-NR1-1R1-2为-N(CH3)2;
和/或,所述的m为3.8-4.2,例如3.88、3.90、3.96、3.97、3.98、4.00、4.03、4.05、4.10、4.12或4.13;
和/或,所述的n为8、9、10、11和12。
4.如权利要求1所述的抗体药物偶联物或其药学上可接受的盐,其特征在于:
R2和R5分别独立地为C1-C6烷基;
和/或,R3和R6分别独立地为卤素;
和/或,R4和R7为乙基;
和/或,所述的L1为苯丙氨酸残基、丙氨酸残基、甘氨酸残基和缬氨酸残基中的一种或多种,优选为缬氨酸残基和/或丙氨酸残基,所述的多种优选为两种或三种;
和/或,所述的R1为被一个或多个-NR1-1R1-2取代的C1~C6烷基、被一个或多个R1-3S(O)2-取代的C1~C6烷基、或、C1~C6烷基,优选为被一个或多个-NR1-1R1-2取代的C1~C6烷基、或、被一个或多个R1-3S(O)2-取代的C1~C6烷基,最优选为被一个或多个R1-3S(O)2-取代的C1~C6烷基;
5.如权利要求1~4中任一项所述的抗体药物偶联物或其药学上可接受的盐,其特征在于,所述的抗体偶联药物为如下任一方案:
方案一:
R2和R5分别独立地为C1-C6烷基;
R1为被一个或多个-NR1-1R1-2取代的C1~C6烷基、被一个或多个R1-3S(O)2-取代的C1~C6烷基、或、C1~C6烷基;
L1为苯丙氨酸残基、丙氨酸残基、甘氨酸残基和缬氨酸残基中的一种或多种;
方案二:
R2和R5分别独立地为C1-C6烷基;
m为3.5-4.5;
R1为被一个或多个-NR1-1R1-2取代的C1~C6烷基、被一个或多个R1-3S(O)2-取代的C1~C6烷基、或、C1~C6烷基;
L1独立地为缬氨酸残基和/或丙氨酸残基;
方案三:
R1为被一个或多个-NR1-1R1-2取代的C1~C6烷基、被一个或多个R1-3S(O)2-取代的C1~C6烷基、或、C1~C6烷基;
L1独立地为缬氨酸残基和/或丙氨酸残基;
方案四:
m为3.5-4.5,
R1为被一个或多个-NR1-1R1-2取代的C1~C6烷基、被一个或多个R1-3S(O)2-取代的C1~C6烷基、或、C1~C6烷基;
L1独立地为缬氨酸残基和/或丙氨酸残基。
9.一种药物组合物,其包括物质X和药用辅料,所述的物质X为如权利要求1~7中任一项所述的抗体药物偶联物或其药学上可接受的盐,所述的物质X的量优选为治疗有效量。
10.一种物质X或如权利要求9所述的药物组合物在制备TROP2蛋白抑制剂中的应用,所述的物质X为如权利要求1~7中任一项所述的抗体药物偶联物或其药学上可接受的盐。
11.一种物质X或如权利要求9所述的药物组合物在制备用于治疗和/或预防肿瘤的药物中的应用,所述的物质X为如权利要求1~7中任一项所述的抗体药物偶联物或其药学上可接受的盐;所述的肿瘤优选TROP2阳性肿瘤;所述的TROP2阳性肿瘤优选TROP2阳性胃癌、三阴乳腺癌和人胰腺癌的一种或多种;胃癌细胞优选为NCI-N87细胞;三阴乳腺癌细胞优选为MDA-MB-468细胞;胰腺癌细胞优选为BXPC3细胞。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202011514030.6A CN114642740A (zh) | 2020-12-18 | 2020-12-18 | 一种靶向trop2的抗体药物偶联物、其制备方法及应用 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202011514030.6A CN114642740A (zh) | 2020-12-18 | 2020-12-18 | 一种靶向trop2的抗体药物偶联物、其制备方法及应用 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN114642740A true CN114642740A (zh) | 2022-06-21 |
Family
ID=81990483
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202011514030.6A Pending CN114642740A (zh) | 2020-12-18 | 2020-12-18 | 一种靶向trop2的抗体药物偶联物、其制备方法及应用 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN114642740A (zh) |
-
2020
- 2020-12-18 CN CN202011514030.6A patent/CN114642740A/zh active Pending
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP7407845B2 (ja) | 抗体薬物複合体、その中間体、製造方法及び使用 | |
JP7488389B2 (ja) | 抗体-薬物コンジュゲートの新規製造方法 | |
KR20200041993A (ko) | 항체-약물 콘주게이트의 개량 제조 방법 | |
CN112237634B (zh) | 抗体药物偶联物、其中间体、制备方法及应用 | |
TW202102225A (zh) | 抗her2抗體-吡咯并苯二氮呯衍生物結合物 | |
CN112138171A (zh) | 抗体偶联药物、其中间体、制备方法及应用 | |
EP4265275A1 (en) | Trop2 targeting antibody-drug conjugate, and preparation method and use therefor | |
CN114642739A (zh) | 一种靶向b7-h3的抗体药物偶联物、其制备方法及应用 | |
CN114601933A (zh) | 抗体药物偶联物、其中间体、制备方法及应用 | |
CN114642740A (zh) | 一种靶向trop2的抗体药物偶联物、其制备方法及应用 | |
RU2822663C1 (ru) | Конъюгат антитело-лекарственное средство, нацеливающийся на trop2, и способ его получения и его применение | |
EP4257153A1 (en) | Antibody-drug conjugate, and intermediate thereof, preparation method therefor, and application thereof | |
EP4265274A1 (en) | B7-h3 targeting antibody-drug conjugate, and preparation method therefor and use thereof | |
RU2800137C1 (ru) | Конъюгат антитело-лекарственное средство, промежуточное соединение для его получения, способ его получения и его применение | |
CN113766933B (zh) | 一种抗体偶联药物、其中间体、制备方法及应用 | |
CN114569738A (zh) | 抗体偶联药物及其中间体和应用 | |
CN115594732A (zh) | 一种连接基-药物偶联物、其制备方法及应用 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination |