CN-121985962-A - Coupling medicine of integrin receptor and its application

Abstract

Polypeptide conjugate compounds with high affinity to an integrin receptor (alpha V beta 3) and pharmaceutically acceptable salts thereof, pharmaceutical compositions containing the same, and use of the pharmaceutical conjugates and pharmaceutical compositions for preparing medicaments for preventing and/or treating diseases in which alpha V beta 3 is overexpressed.

Inventors

• LI YAO
• CHEN LEI
• ZHANG HAOLIANG
• HUANG HAITAO
• ZHANG CHEN
• YAN PANGKE

Assignees

• 海思科医药集团股份有限公司

Dates

Publication Date

20260505

Application Date

20241011

Priority Date

20231011

Claims (11)

1. A drug conjugate represented by formula (I) or a stereoisomer, a pharmaceutically acceptable salt thereof, P-L-D (I) Wherein, P is selected from RGD peptide, and comprises linear polypeptide and cyclic polypeptide containing RGD peptide sequence; l is a linker; D is a cytotoxic agent.
2. The drug conjugate or stereoisomer, pharmaceutically acceptable salt thereof according to claim 1, wherein the cytotoxic agent is selected from the group consisting of alkylating agents, antimetabolites, plant alkaloids, terpenoids, podophyllotoxins and derivatives thereof, taxanes and derivatives thereof, topoisomerase inhibitors, tubulin polymerization inhibitors, RNA polymerase inhibitors, antitumor antibiotics.
3. The drug conjugate of claim 2, or a stereoisomer, pharmaceutically acceptable salt thereof, wherein the cytotoxic agent is selected from the group consisting of cisplatin, carboplatin, oxaliplatin, nitrogen mustard, cyclophosphamide, chlorambucil, ifosfamide, azathioprine, mercaptopurine, pyrimidine analogs, vincristine, vinblastine, vinorelbine, vindesine, etoposide, teniposide, paclitaxel, camptothecin, irinotecan, topotecan, an Ya th, etoposide, teniposide phosphate, actinomycin D, doxorubicin, epirubicin, eribulin, lubidine, trabectedin, epothilone and derivatives thereof, bleomycin and derivatives thereof, dactinomycin and derivatives thereof, plicamycin and derivatives thereof, mitomycin C, spinocetin and derivatives thereof, and aureostatin and derivatives thereof.
4. A drug conjugate according to claim 3, or a stereoisomer, pharmaceutically acceptable salt thereof, wherein the cytotoxic agent is selected from docetaxel, MMAE, 7-ethylcamptothecin, irinotecan, dxd, eribulin, lubidine or qu Bei Ti.
5. The drug conjugate of claim 1, or a stereoisomer, pharmaceutically acceptable salt thereof, wherein the linker is selected from one or a combination of several of the following groups: unmodified or modified monoamino acids, unmodified or modified amino acid chains of different lengths, alkyl chains with or without O, N heteroatoms, M, n, p, q, u are each independently selected from integers from 0 to 20; v is selected from integers from 1 to 100; t is selected from integers from 1 to 150; r is selected from integers from 0 to 150.
6. The drug conjugate of claim 5, or a stereoisomer, pharmaceutically acceptable salt thereof, wherein the linker is selected from the group consisting of: Wherein, the Represents the site of the L-to-P linkage and the site of the P-to-D linkage.
7. A drug conjugate, or a stereoisomer, pharmaceutically acceptable salt thereof, the drug conjugate being selected from one of the following structures,
8. A pharmaceutical composition or pharmaceutical formulation comprising a conjugated compound according to any one of claims 1 to 7, or a stereoisomer, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier and/or excipient.
9. A pharmaceutical composition or pharmaceutical formulation according to claim 8, comprising a coupling compound according to any one of claims 1 to 7, or a stereoisomer, pharmaceutically acceptable salt and carrier and/or excipient thereof, in an amount selected from 1 to 1500 mg.
10. Use of a drug conjugate according to any one of claims 1-7 or a stereoisomer, pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 8 or 9 for the preparation of a medicament for the prevention and/or treatment of a disease that overexpresses αvβ3, preferably a disease that overexpresses αvβ3 is selected from cancer.
11. A method for treating a disease in a mammal or a human, the method comprising administering to a subject a therapeutically effective amount of a conjugate compound of any one of claims 1-7, a stereoisomer, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 8 or 9, the therapeutically effective amount preferably being 1-1500mg, the disease preferably being cancer, more preferably the disease being colon cancer, lung cancer, breast cancer, ovarian cancer, pancreatic cancer, gastric cancer, brain glioma and malignant sarcomas, carcinomas and lymphomas of the breast, ovary, colon, kidney, liver gall, lung and brain.

Description

Coupling medicine of integrin receptor and its application Technical Field The invention belongs to the field of antitumor drugs, and in particular relates to an integrin receptor-targeted polypeptide coupling drug, a preparation method and application thereof. Background A large number of researches show that the molecular expression states of tumor cells and tumor vascular endothelial cells are greatly different from those of normal cells, so that the distinction of tumor tissues and normal tissues is possible. The targeting peptide is used as a carrier, PDC (polypeptide coupled medicine) is formed by chemical connection with cytotoxin, the peptides are used for specifically targeting tumor cells, and the carried anticancer drug molecules are released in specific physiological environments (such as low pH, high-expression protease and high reducibility) of tumor cells or tissues. The receptor targeting PDC obtained based on the mechanism has shown more effective tumor treatment effect than the free chemical drug molecules of unconjugated polypeptide in various tumor models such as breast cancer, prostatic cancer, melanoma and the like. Disclosure of Invention The invention provides conjugated compounds specific to alpha V beta 3, which have high affinity to targets, good selectivity, high stability, excellent pharmacokinetics, and have the beneficial characteristics of being suitable for injection, inhalation, nose, eyes, oral administration or local administration, and the like. Specifically, the invention provides a drug conjugate shown in a formula (I) or stereoisomer and pharmaceutically acceptable salt thereof, P-L-D (I) Wherein, P is selected from RGD peptide, and comprises linear polypeptide and cyclic polypeptide containing RGD peptide sequence; In some embodiments, P is selected from iRGD, cRGD; in some embodiments, P is selected from iRGD, cRGDyC, cRGDyK, cRGDfC, cRGDfK; In some embodiments, P is selected from L is a linker, D is a cytotoxic agent; In some embodiments, the cytotoxic agent is selected from the group consisting of alkylating agents, antimetabolites, plant alkaloids, terpenoids, podophyllotoxins and derivatives thereof, taxanes and derivatives thereof, topoisomerase inhibitors, tubulin polymerization inhibitors, RNA polymerase inhibitors, antitumor antibiotics; in some embodiments, the cytotoxic agent is selected from the group consisting of cisplatin, carboplatin, oxaliplatin, nitrogen mustard, cyclophosphamide, chlorambucil, ifosfamide, azathioprine, mercaptopurine, pyrimidine analogs, vincristine, vinblastine, vinorelbine, vindesine, etoposide, teniposide, paclitaxel, camptothecin, irinotecan, an Ya pyridine, etoposide phosphate, teniposide, actinomycin D, doxorubicin, epirubicin, eribulin, lubidine, trabectedin, epothilone and derivatives thereof, bleomycin and derivatives thereof, dactinomycin and derivatives thereof, plicamycin and derivatives thereof, mitomycin C, spinocetin, maytansine and derivatives thereof, austrastatin and derivatives thereof; in some embodiments, the cytotoxic agent is selected from the group consisting of cisplatin, carboplatin, oxaliplatin, nitrogen mustard, cyclophosphamide, chlorambucil, ifosfamide, azathioprine, mercaptopurine, pyrimidine analogs, vincristine, vinblastine, vinorelbine, vindesine, etoposide, teniposide, paclitaxel, camptothecin, irinotecan, topotecan, an Ya pyridine, etoposide, teniposide, actinomycin D, doxorubicin, epirubicin, eribulin, lubidine, leupeptine, irinotecan, and combinations thereof, trabectedin, epothilone and derivatives thereof, bleomycin and derivatives thereof, dactinomycin and derivatives thereof, plicamycin and derivatives thereof, mitomycin C, spinocerebirth, maytansine and derivatives thereof, auristatin and derivatives thereof; in some embodiments, the cytotoxic agent is selected from docetaxel, MMAE, 7-ethylcamptothecin, irinotecan, dxd, eribulin, lubidine, or qu Bei Ti, and in some embodiments, the cytotoxic agent is selected from docetaxel, MMAE, 7-ethylcamptothecin, irinotecan, dxd, eribulin, lubidine, or qu Bei Ti; in some embodiments, the cytotoxic agent is selected from the following structures: in some embodiments, the cytotoxic agent is selected from the following structures: In some embodiments, the linker is selected from the group consisting of an unmodified or modified single amino acid, an unmodified or modified chain of amino acids of different lengths, an alkyl chain with or without O, N heteroatoms, a combination of one or more of, M, n, p, q, u are each independently selected from integers from 0 to 20; v is selected from integers from 1 to 100; t is selected from integers from 1 to 150; r is selected from integers from 0 to 150; In some embodiments, the linker is selected from the group consisting of an unmodified or modified single amino acid, an unmodified or modified chain of amino acids of different lengths, an alkyl chain with or without O, N heteroatoms, a combination of one or more