WO2023066314A1 - Ligand peptidique bicyclique pour nectine-4 et son utilisation - Google Patents

Ligand peptidique bicyclique pour nectine-4 et son utilisation Download PDF

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WO2023066314A1
WO2023066314A1 PCT/CN2022/126245 CN2022126245W WO2023066314A1 WO 2023066314 A1 WO2023066314 A1 WO 2023066314A1 CN 2022126245 W CN2022126245 W CN 2022126245W WO 2023066314 A1 WO2023066314 A1 WO 2023066314A1
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hcys
cys
seq
compound
asp
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PCT/CN2022/126245
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Chinese (zh)
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李瑶
陈雷
黄海涛
唐平明
余彦
张晨
严庞科
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海思科医药集团股份有限公司
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Priority to CN202280070651.0A priority Critical patent/CN118201627A/zh
Publication of WO2023066314A1 publication Critical patent/WO2023066314A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to a compound containing polypeptide structure with high affinity for cell adhesion molecule (Nectin-4) and its polypeptide drug conjugate conjugated to one or more toxin molecules, and the compound and drug conjugate Related uses of the drug, including the use of preparing pharmaceutical compositions and the use of preventing and/or treating diseases or diseases in which Nectin-4 is overexpressed in diseased tissues of tumor individuals.
  • Nectin-4 cell adhesion molecule
  • Nectin is a cell adhesion molecule belonging to a Ca2 + -independent immunoglobulin (Immunoglobulin, Ig) superfamily, and is a homologue of the poliovirus receptor (PVR/CD155), also known as poliovirus Inflammatory virus receptor related protein (Pliovirus Receptor Related Protein, PVRL).
  • Nectin family consists of four members Nectin 1-Nectin 4. Nectin is widely expressed in organisms, Nectin-1, Nectin-2 and Nectin-3 are expressed in a variety of cells, including: fibroblasts, epithelial cells and neuronal cells.
  • Nectin-2 and Nectin-3 are also expressed in cells lacking cadherin glycoproteins, such as B cells, monocytes and sperm cells.
  • the expression of human Nectin-4 is mainly in embryonic development stage and tumor tissue, but not in adult normal tissue.
  • Nectin-4 belongs to the cell membrane surface receptor, which can affect the tight junction between cells, participate in the adhesion between cells, and then regulate activities such as cell movement, differentiation and virus invasion. In recent years, the relationship between Nectin-4 and tumors has been paid close attention by researchers. For example, Takano et al. reported that Nectin-4 can promote the growth and proliferation of tumor cells through the Rac1 signaling pathway. In breast cancer, Nectin-4 was identified as an independent adverse prognostic factor in triple-negative breast cancer.
  • Nectin-4 Although the mechanism of action of Nectin-4 in tumor biology and cancer progression is still unclear, as a new type of tumor-associated antigen, its clinical potential is huge, which provides opportunities for the development of new therapeutic drugs (such as nucleic acid drugs, monoclonal antibodies) a great possibility.
  • new therapeutic drugs such as nucleic acid drugs, monoclonal antibodies
  • PADCEV Enfortumab vedotin
  • the human IgG1 monoclonal antibody enfortumab is conjugated with the cytotoxic agent MMAE (monomethyl auristatin E, a microtubule disruptor), and it is also the only Nectin-4 targeting medicine.
  • MMAE monomethyl auristatin E, a microtubule disruptor
  • the present invention provides a compound with high affinity for cell adhesion molecule (Nectin-4), which comprises a polypeptide structure, and also provides a polypeptide drug conjugate in which the compound is conjugated to one or more toxin molecules, and Provided are pharmaceutical compositions, and their related uses in preventing and/or treating diseases or conditions in which Nectin-4 is overexpressed in diseased tissues of tumor individuals.
  • Nectin-4 cell adhesion molecule
  • the present invention relates to a compound comprising a polypeptide structure and a non-aromatic molecular scaffold, the polypeptide structure comprising at least three residues selected from Cys and Hcys separated by at least two amino acid sequences, and the Cys or Hcys
  • the residue forms a covalent bond with the non-aromatic molecular scaffold, thereby forming at least two polypeptide rings on the molecular scaffold; the condition is that the residues of Cys and Hcys contain at least one Hcys residue.
  • the compound comprises a polypeptide structure and a non-aromatic molecular scaffold
  • the polypeptide structure comprises at least three residues selected from Cys and Hcys separated by at least two amino acid sequences, and wherein Two are Hcys residues, and the Cys or Hcys residues form a covalent bond with the non-aromatic molecular scaffold, thereby forming at least two polypeptide loops on the molecular scaffold.
  • the compound comprises a polypeptide structure and a non-aromatic molecular scaffold
  • the polypeptide structure comprises at least three residues selected from Cys and Hcys separated by at least two amino acid sequences, and wherein One is a Hcys residue, and the Cys or Hcys residue forms a covalent bond with the non-aromatic molecular scaffold, thereby forming at least two polypeptide loops on the molecular scaffold.
  • the non-aromatic molecular scaffold is selected from TATA and TATB.
  • the compound comprises a polypeptide structure and a non-aromatic molecular scaffold
  • the polypeptide structure comprises at least three residues selected from Cys and Hcys separated by at least two amino acid sequences, and wherein Two are Hcys residues, and the Cys or Hcys residues form a covalent bond with the non-aromatic molecular scaffold to form at least two polypeptide rings on the molecular scaffold
  • the molecular scaffold is selected from TATA.
  • the compound comprises a polypeptide structure and a non-aromatic molecular scaffold
  • the polypeptide structure comprises at least three residues selected from Cys and Hcys separated by at least two amino acid sequences, and wherein One is the Hcys residue, the Cys or Hcys residue forms a covalent bond with the non-aromatic molecular scaffold to form at least two polypeptide rings on the molecular scaffold, and the molecular scaffold is selected from TATA.
  • the compound comprises a polypeptide structure and a non-aromatic molecular scaffold
  • the polypeptide structure comprises at least three residues selected from Cys and Hcys separated by at least two amino acid sequences, and wherein Two are Hcys residues, and the Cys or Hcys residues form a covalent bond with the non-aromatic molecular scaffold to form at least two polypeptide rings on the molecular scaffold
  • the molecular scaffold is selected from TATB.
  • the compound comprises a polypeptide structure and a non-aromatic molecular scaffold
  • the polypeptide structure comprises at least three residues selected from Cys and Hcys separated by at least two amino acid sequences, and wherein One is the Hcys residue, the Cys or Hcys residue forms a covalent bond with the non-aromatic molecular scaffold to form at least two polypeptide rings on the molecular scaffold, and the molecular scaffold is selected from TATB.
  • polypeptide structure of the compound comprises the following amino acid sequence:
  • A1, A2 represent the amino acid sequence between Xa1, Xa2, and Xa3, and A1 and A2 each independently contain 3-10 amino acid residues; in some specific embodiments, the amino acid residues contained in A1, A2 are optionally is selected from Pro(P), 1Nal, D-Asp, Met(M), HArg, Asp(D), Trp(W), Ser(S), Thr(T), Hyp, Val, Ile and Gly, etc.;
  • Xa1, Xa2, and Xa3 are independently Cys or Hcys residues, and at least one of them is an Hcys residue, and the non-aromatic molecular scaffold forms a thioether bond with Xa1, Xa2, and Xa3 of the polypeptide respectively, thereby forming a thioether bond in the molecule Two polypeptide loops are formed on the scaffold.
  • one of said A1 and A2 consists of 3 amino acid residues, and the other consists of 9 amino acid residues; in some specific embodiments, said A1 consists of 3 amino acid residues Composition, A2 consists of 9 amino acid residues; in some specific embodiments, said A1 consists of 9 amino acid residues, and A2 consists of 3 amino acid residues.
  • polypeptide structure comprises the amino acid sequence shown below:
  • Xa1, Xa2, Xa3 are respectively selected from Cys or Hcys; the condition is Xa1, Xa2, Xa3 At least one selected from Hcys.
  • polypeptide structure comprises the amino acid sequence shown in any one of SEQ ID NO:1 ⁇ SEQ ID NO:7:
  • polypeptide structure comprises the amino acid sequence shown in any one of SEQ ID NO:8 ⁇ SEQ ID NO:14:
  • the compound is a bicyclic peptide containing one of the following structures, optionally containing other amino acid sequences at the N-terminus and/or C-terminus of the following structures:
  • n1, n2, and n3 are 1 or 2 independently.
  • the compound is a bicyclic peptide having one of the following structures, wherein the bicyclic is as described above (such as I-1 or II-1), and n4 is any integer from 0 to 10, such as 3, 4, 5, 6, 7, 8, 9, 10, in some embodiments, n4 is 9:
  • the compound is a bicyclic peptide having one of the following structures:
  • n4 is selected from any integer of 0-10.
  • the bicyclic peptide of formula I-2 or II-2 wherein,
  • Xa1 is Hcys, m1 is 2, n1 is 1 or 2, and n4 is 9; or
  • Xa2 is Hcys, m2 is 2, n2 is 1 or 2, and n4 is 9; or
  • Xa3 is Hcys, m3 is 2, n3 is 1 or 2, and n4 is 9.
  • the compound is selected from one of the structures in Table 1:
  • the compound comprising at least two polypeptide ring structures of the present invention has protein stability and is stable to plasma protease, epithelial protease, gastric and intestinal protease, lung surface protease, intracellular protease, etc.; has specific targeting to Nectin-4, It is a peptide ligand specific to Nectin-4; it has a longer plasma half-life, and has good pharmacokinetic and pharmacodynamic properties.
  • the present invention also provides the application of the compound as a ligand of Nectin-4 in screening and/or preparing medicine.
  • the present invention also provides a drug conjugate or a pharmaceutically acceptable salt thereof, said conjugate comprising a compound as described above conjugated to one or more effectors and/or functional groups via a linker.
  • said effector is a cytotoxic agent.
  • the present invention provides a drug conjugate represented by formula II or a pharmaceutically acceptable salt thereof,
  • the cytotoxic agent is selected from one or more of the following group: alkylating agents, antimetabolites, plant alkaloids, terpenoids, podophyllotoxins, and Derivatives, taxanes and their derivatives, topoisomerase inhibitors, antitumor antibiotics.
  • the cytotoxic agent is selected from the group consisting of alkylating agents, antimetabolites, plant alkaloids, terpenoids, podophyllotoxins and derivatives thereof, taxanes Classes and their derivatives, topoisomerase inhibitors, antitumor antibiotics.
  • the linker is a divalent, trivalent, tetravalent or pentavalent spacer moiety linking the cytotoxic agent moiety and the peptide ligand moiety.
  • the linker is a bivalent spacer moiety linking the cytotoxic agent moiety and the peptide ligand moiety; wherein the peptide ligand is linked to one cytotoxic agent moiety through the linker.
  • the linker is a trivalent spacer moiety connecting the cytotoxic agent moiety and the peptide ligand moiety; wherein the peptide ligand is independently linked to the two cytotoxic agent moieties through the linker.
  • the linker is a tetravalent spacer moiety linking the cytotoxic agent moiety and the peptide ligand moiety; wherein the peptide ligand is independently linked to the three cytotoxic agent moieties through the linker.
  • the linker is a pentavalent spacer moiety connecting the cytotoxic agent moiety and the peptide ligand moiety; wherein the peptide ligand is independently linked to the four cytotoxic agent moieties through the linker.
  • the peptide ligand is a compound as described above.
  • the cytotoxic agent is selected from the group consisting of cisplatin, carboplatin, oxaliplatin, nitrogen mustard, cyclophosphamide, chlorambucil, ifosfamide, sulfur Azathioprine, mercaptopurine, pyrimidine analogs, vincristine, vinblastine, vinorelbine, vindesine, etoposide, teniposide, paclitaxel, camptothecin and its derivatives, irinotecan, toposide Tecan, Amyridine, Etoposide, Etoposide Phosphate, Teniposide, Actinomycin D, Doxorubicin, Epirubicin, Epothilone and its derivatives, Bleomycin and its derivatives, dactinomycin and its derivatives, plicamycin and its derivatives, mitomycin C, cyspamicin, maytansine and its derivatives, auristatin and its
  • the cytotoxic agent is selected from maytansinoids, monomethyl auristatin, or camptothecin derivatives. In some embodiments, the cytotoxic agent is selected from maytansinoids or monomethyl auristatin. In some embodiments, the cytotoxic agent is selected from maytansine DM1, monomethylauristatin E (MMAE), or 7-ethyl-10-hydroxycamptothecin (SN38). In some embodiments, the cytotoxic agent is selected from DM1 or MMAE. In some embodiments, the cytotoxic agent is selected from MMAE.
  • linker is a peptide linker, a disulfide linker or a pH-dependent linker.
  • the disulfide linker is selected from DMDS, MDS, DSDM, NDMDS or the structure of formula III:
  • R 1 , R 2 , R 3 and R 4 are independently selected from H, methyl, ethyl, propyl and isopropyl;
  • p and q are independently 1, 2, 3, 4 or 5;
  • the peptide linker is selected from: -Cit-Val-, -Phe-Lys- and -Val-Lys-;
  • the pH-dependent linker is selected from cis-aconitic anhydride.
  • the above-mentioned linkers are mainly used to connect cytotoxic agents and peptide ligands, and to release toxic substances under specific conditions.
  • the linkers can be appropriately modified, such as in its
  • the linker of the present invention includes linker derivatives modified based on the above-mentioned links to link some groups to increase the chain length, and to increase group modification around the cleavage bond to control the hindrance of the cleavage bond.
  • the linker can theoretically be connected to the N-terminal, C-terminal and/or molecular scaffold of the peptide ligand.
  • a functional group linked to it can be modified on the C-terminal or molecular scaffold.
  • linker is -PABC-Cit-Val-glutaryl-, -PABC-cyclobutyl-Ala-Cit- ⁇ Ala- or Wherein PABC represents p-aminobenzyl carbamate; k is selected from any integer of 1-20.
  • linker is -PABC-Cit-Val-glutaryl- or -PABC-cyclobutyl-Ala-Cit- ⁇ Ala-, wherein PABC represents p-aminobenzylcarbamate ester.
  • linker is Wherein k is selected from any integer of 1-20.
  • k is selected from any integer of 1-20; in some specific embodiments, k is selected from any integer of 1-10; in some specific embodiments, k is selected from 1, 2, 3, 4 or 5.
  • the drug conjugate has the structure of Formula III-1, Formula III-2, Formula III-3 or Formula III-4:
  • Xa1, Xa2, and Xa3 are independently Cys or Hcys residues, and at least one of them is a Hcys residue;
  • n1, n2, n3 are independently 1 or 2;
  • n4 is selected from any integer of 0-10;
  • k is selected from any integer of 1-10.
  • Xa1 is Hcys, m1 is 2, n1 is 1 or 2, and n4 is 9; or
  • Xa2 is Hcys, m2 is 2, n2 is 1 or 2, and n4 is 9; or
  • Xa3 is Hcys, m3 is 2, n3 is 1 or 2, and n4 is 9.
  • the present invention relates to a drug conjugate or a pharmaceutically acceptable salt thereof, wherein the drug conjugate is selected from one of the following structures:
  • the present invention also relates to a pharmaceutical composition, which comprises the aforementioned compound of the present invention (i.e. peptide ligand, or peptide compound) and/or the aforementioned drug conjugate of the present invention or its pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier and/or excipient.
  • a pharmaceutical composition which comprises the aforementioned compound of the present invention (i.e. peptide ligand, or peptide compound) and/or the aforementioned drug conjugate of the present invention or its pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier and/or excipient.
  • the present invention also relates to a use of the aforementioned compound of the present invention, or the aforementioned drug conjugate of the present invention or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the preparation of prevention and/or treatment of tumors Use in medicine for diseases or conditions in which Nectin-4 is overexpressed in diseased tissues of an individual.
  • said individual is a mammal or a human.
  • the disease overexpressing Nectin-4 is cancer.
  • cancers and their benign counterparts that can be treated (or inhibited) include, but are not limited to, tumors of epithelial origin (adenomas and various types of carcinomas, including adenocarcinoma, squamous cell carcinoma, transitional cell carcinoma, and others ), such as bladder and urinary tract, breast, gastrointestinal (including esophagus, stomach (stomach), small intestine, colon, rectum, and anus), liver (hepatocellular), gallbladder, and biliary tract Systemic cancer, exocrine pancreatic cancer, renal cancer, lung cancer (such as adenocarcinoma, small cell lung cancer, non-small cell lung cancer, bronchoalveolar carcinoma, and mesothelioma), head and neck cancer (such as tongue cancer, buccal cavity cancer, laryngeal cancer, pharyngeal cancer , nasopharyngeal cancer, tonsil
  • the disease or disease overexpressing Nectin-4 is at least one of urothelial cancer, breast cancer, ovarian cancer, gastric cancer, esophageal cancer, hepatocellular carcinoma, pancreatic cancer, triple-negative breast cancer and bladder cancer .
  • the present invention also relates to a pharmaceutical composition or pharmaceutical preparation, said pharmaceutical composition or pharmaceutical preparation comprising 1-1500 mg of the aforementioned compound of the present invention or the aforementioned conjugate of the present invention or its pharmaceutically acceptable Acceptable salts, and pharmaceutically acceptable carriers and/or excipients.
  • the present invention also relates to a method for treating diseases in mammals or humans, the method comprising administering to a subject a therapeutically effective amount of the aforementioned compound of the present invention or the aforementioned conjugate of the present invention or its pharmaceutical
  • the therapeutically effective dose is preferably 1-1500 mg, and the disease is preferably tumor.
  • the present invention also provides a composition or pharmaceutical preparation, which contains the peptide compound, conjugate or pharmaceutically acceptable salt thereof described in any one of the preceding schemes, and a pharmaceutically acceptable carrier and/or adjuvant.
  • the pharmaceutical composition may be in unit dosage form (a unit dosage is also referred to as a "dosage strength").
  • composition or pharmaceutical preparation of the present invention contains 1-1500 mg of the peptide compound, conjugate or pharmaceutically acceptable salt thereof described in any one of the preceding schemes, and a pharmaceutically acceptable carrier and/or or accessories.
  • the present invention also provides preparations of the peptide compound, conjugate or pharmaceutically acceptable salt thereof described in any one of the preceding schemes for the prevention and/or treatment of diseases or conditions in which Nectin-4 is overexpressed in diseased tissues of tumor individuals Uses in medicine.
  • the disease or disease overexpressing Nectin-4 is preferably at least one of urothelial cancer, breast cancer, ovarian cancer, gastric cancer, esophageal cancer, hepatocellular carcinoma, pancreatic cancer, triple-negative breast cancer and bladder cancer kind.
  • said individual is a mammal or a human.
  • the present invention also provides a method for treating diseases in mammals or humans, the method comprising administering to a subject a therapeutically effective amount of the peptide compound, conjugate or pharmaceutically acceptable amount thereof described in any one of the preceding schemes.
  • Acceptable salts the disease is preferably at least one of urothelial cancer, breast cancer, ovarian cancer, gastric cancer, esophageal cancer, hepatocellular carcinoma, pancreatic cancer, triple negative breast cancer and bladder cancer, preferably the treatment is effective
  • the amount is 1-1500 mg.
  • Effective amount or “therapeutically effective amount” in the present application refers to the administration of a sufficient amount of the compound disclosed in the present application, which will alleviate to some extent one or more symptoms of the disease or disorder being treated. In some embodiments, the result is reduction and/or alleviation of signs, symptoms or causes of disease, or any other desired alteration of a biological system.
  • an "effective amount” for therapeutic use is the amount of a composition comprising a peptide compound disclosed herein, a conjugate, or a pharmaceutically acceptable salt thereof, required to provide a clinically significant reduction in disease symptoms.
  • therapeutically effective amounts include, but are not limited to, 1-1500 mg, 1-1400 mg, 1-1300 mg, 1-1200 mg, 1-1000 mg, 1-900 mg, 1-800 mg, 1-700 mg, 1-600 mg, 1-500 mg, 1 -400mg, 1-300mg, 1-250mg, 1-200mg, 1-150mg, 1-125mg, 1-100mg, 1-80mg, 1-60mg, 1-50mg, 1-40mg, 1-25mg, 1-20mg , 5-1500mg, 5-1000mg, 5-900mg, 5-800mg, 5-700mg, 5-600mg, 5-500mg, 5-400mg, 5-300mg, 5-250mg, 5-200mg, 5-150mg, 5 -125mg, 5-100mg, 5-90mg, 5-70mg, 5-80mg, 5-60mg, 5-50mg, 5-40mg, 5-30mg, 5-25mg, 5-20mg, 10-1500mg, 10-1000mg 10-900
  • the pharmaceutical composition or preparation of the present invention contains the aforementioned therapeutically effective amount of the peptide compound, conjugate or pharmaceutically acceptable salt thereof of the present invention.
  • the present invention relates to a pharmaceutical composition or pharmaceutical preparation, which comprises a therapeutically effective amount of the peptide compound, conjugate or pharmaceutically acceptable salt thereof and a carrier and/or excipient.
  • the pharmaceutical composition may be in the form of a unit preparation (the amount of the main drug in the unit preparation is also referred to as "preparation specification").
  • the pharmaceutical composition includes, but is not limited to, 1 mg, 1.25 mg, 2.5 mg, 5 mg, 10 mg, 12.5 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg ,70mg,75mg,80mg,85mg,90mg,95mg,100mg,110mg,120mg,125mg,130mg,140mg,150mg,160mg,170mg,180mg,190mg,200mg,210mg,220mg,230mg,240mg,250mg,275mg,300mg , 325mg, 350mg, 375mg, 400mg, 425mg, 450mg, 475mg, 500mg, 525mg, 550mg, 575mg, 600mg, 625mg, 650mg, 675mg, 700mg, 725mg, 750
  • the present invention provides 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 peptide compound, conjugate, or pharmaceutically acceptable compound of the present invention salt, and pharmaceutically acceptable carriers and/or excipients, the therapeutically effective dose is preferably 1-1500 mg, and the diseases are preferably urothelial cancer, breast cancer, ovarian cancer, gastric cancer, esophageal cancer, hepatocellular carcinoma, At least one of pancreatic cancer, triple-negative breast cancer, and bladder cancer.
  • the present invention provides a method for treating a disease in a mammal or a human, the method comprising administering the peptide compound of the present invention, the conjugate or a pharmaceutically acceptable salt thereof, and a pharmaceutical Acceptable carriers and/or excipients above are given to the subject at a daily dose of 1-1500 mg/day, and the daily dose can be a single dose or divided doses.
  • the daily dose includes but is not limited to 10-1500mg/day, 20-1500mg/day, 25-1500mg/day, 50-1500mg/day, 75-1500mg/day, 100-1500mg/day, 200-1500mg/day, 10-1000mg/day, 20- 1000mg/day, 25-1000mg/day, 50-1000mg/day, 75-1000mg/day, 100-1000mg/day, 200-1000mg/day, 25-800mg/day, 50-800mg/day, 100-800mg/day day, 200-800mg/day, 25-400mg/day, 50-400mg/day, 100-400mg/day, 200-400mg/day, in some embodiments, the daily dosage includes but not limited to 1mg/day, 5mg/day day, 10mg/day, 20mg/day, 25mg/day, 50mg/day, 75mg/day, 100mg/day, 125mg
  • the present invention also provides a kit, which may include a composition in single dose or multi-dose form, the kit comprising a compound of the present invention, a conjugate or a pharmaceutically acceptable salt thereof, a compound of the present invention, a conjugate, or a pharmaceutically acceptable salt thereof.
  • the amount of the conjugate or pharmaceutically acceptable salt is the same as that in the above-mentioned pharmaceutical composition.
  • Preparation specification refers to the weight of the main drug contained in each tube, tablet or other unit preparation.
  • the peptide moieties of the invention can be prepared synthetically by standard techniques and then reacted with molecular scaffolds in vitro. When doing this, standard chemistry can be used. This enables rapid large-scale preparation of soluble materials for further downstream experiments or validation. Such methods can be achieved using conventional chemistry as disclosed in, for example, Timmerman et al. (2005, ChemBioChem).
  • the drug conjugates of the present invention are synthesized according to the following route:
  • Peptide ligands refer to compounds containing amino acid sequences (peptide structures) formed by covalently binding peptides to molecular scaffolds, and can be used as ligands for cell adhesion molecules (Nectin-4) in the present invention.
  • the peptides forming such compounds contain two or more reactive groups (i.e. cysteine residues and/or homocysteine residues) capable of forming covalent bonds (e.g. thioether bonds) with the scaffold. group), and the relative sequence between the reactive groups (in the present invention, it may also be referred to as a loop sequence).
  • the peptide comprises at least three cysteine residues and/or homocysteine residues (Cys residues and/or Hcys residues), which form at least two loops on the scaffold .
  • Molecular scaffolds include non-aromatic molecular scaffolds.
  • a non-aromatic molecular scaffold refers to any molecular scaffold as defined herein that does not contain an aromatic carbocyclic or aromatic heterocyclic ring system. Examples of suitable non-aromatic molecular scaffolds are described in Heinis et al. (2014) Angewandte Chemie, International Edition 53(6) 1602-1606.
  • Molecular scaffolds can be small molecules, such as small organic molecules.
  • Molecular scaffolds can also be macromolecules, and in some cases, molecular scaffolds are macromolecules composed of amino acids, nucleotides, or carbohydrates. In some cases, the molecular scaffold comprises a reactive group capable of reacting with a functional group of the polypeptide to form a covalent bond.
  • Molecular scaffolds can include chemical groups that form linkages with peptides, such as amines, thiols, alcohols, ketones, aldehydes, nitriles, carboxylic acids, esters, alkenes, alkynes, azides, anhydrides, succinimides, maleic imides, alkyl halides and acid halides.
  • An example of a compound containing an ⁇ unsaturated carbonyl group is 1,1',1"-(1,3,5-triazinane-1,3,5-triyl)triprop-2-en-1-one (TATA ) (Angewandte Chemie, International Edition (2014), 53(6), 1602-1606).
  • non-aromatic molecular scaffolds described herein can be selected from the following structures:
  • non-aromatic skeletons in WO2018197893 can also be selected.
  • Polypeptide refers to a compound formed by linking three or more amino acid molecules together by peptide bonds.
  • the unit of amino acid in a polypeptide is called an amino acid residue.
  • Effectors and/or functional groups are pharmacologically or functionally specific molecules or fragments that can be attached (via a linker) to, for example, the N- and/or C-termini of a polypeptide, amino acids within a polypeptide, or the molecular backbone.
  • Suitable effectors and/or functional groups include antibodies and parts or fragments thereof, cytotoxic molecules or fragments, enzyme inhibitor molecules or fragments, metal chelators, and the like.
  • the effector and/or functional group is a drug, particularly a cytotoxic agent.
  • Derivatives refer to products derived from the substitution of hydrogen atoms or atomic groups in a compound by other atoms or atomic groups.
  • Maytansinoids such as DM1
  • cytotoxic agents which are thiol-containing derivatives of maytansine
  • DM1 has the following structure:
  • MMAE Monomethyl auristatin E
  • the carbon, hydrogen, oxygen, sulfur, nitrogen or halogen involved in the groups and compounds of the present invention include their isotopes, and the carbon, hydrogen, oxygen, sulfur, Nitrogen or halogen is optionally further replaced by one or more of their corresponding isotopes, wherein isotopes of carbon include 12 C, 13 C and 14 C, isotopes of hydrogen include protium (H), deuterium (deuterium, also known as deuterium ), tritium (T, also known as tritium), the isotopes of oxygen include 16 O, 17 O and 18 O, the isotopes of sulfur include 32 S, 33 S, 34 S and 36 S, and the isotopes of nitrogen include 14 N and 15 N, the isotope of fluorine is 19 F, the isotope of chlorine includes 35 Cl and 37 Cl, and the isotope of bromine includes 79 Br and 81 Br.
  • isotopes of carbon include 12 C, 13 C and 14 C
  • “Pharmaceutically acceptable salt” means that the compound of the present invention maintains the biological effectiveness and characteristics of the free acid or free base, and the free acid is mixed with a non-toxic inorganic base or organic base, and the free base is mixed with a non-toxic inorganic base or organic base.
  • Non-toxic salts obtained by reacting inorganic or organic acids.
  • “Pharmaceutical composition” means a mixture of one or more compounds described herein, or stereoisomers, solvates, pharmaceutically acceptable salts or co-crystals thereof, with other constituents, wherein the other constituents comprise physiological/pharmaceutical acceptable carriers and/or excipients.
  • Carrier refers to: does not cause significant irritation to the organism and does not eliminate the biological activity and characteristics of the administered compound, and can change the way the drug enters the body and its distribution in the body, controls the release rate of the drug and releases the drug.
  • Non-limiting examples of systems for delivery to targeted organs include microcapsules and microspheres, nanoparticles, liposomes, and the like.
  • Excipient means: not itself a therapeutic agent, used as a diluent, adjuvant, binder and/or vehicle, added to a pharmaceutical composition to improve its handling or storage properties or to allow or facilitate The compound or pharmaceutical composition is presented in unit dosage form for administration.
  • pharmaceutical excipients can serve various functions and can be described as wetting agents, buffers, suspending agents, lubricants, emulsifiers, disintegrating agents, absorbing agents, preservatives , surfactants, coloring agents, flavoring agents and sweeteners.
  • Examples of pharmaceutically acceptable excipients include, but are not limited to: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as carboxymethyl Sodium cellulose, ethyl cellulose, cellulose acetate, hydroxypropyl methylcellulose, hydroxypropyl cellulose, microcrystalline cellulose, and croscarmellose (such as croscarmellose sodium) (4) tragacanth powder; (5) malt; (6) gelatin; (7) talc; (8) excipients such as cocoa butter and suppository wax; (9) oils such as peanut oil, cottonseed oil, red Flower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as oil (13) a
  • Figure 1 is the tumor growth curve of the mouse NCI-H292 subcutaneous and in vivo xenograft model.
  • Fig. 2 is a curve of the body weight change of the mouse NCI-H292 subcutaneous and in vivo xenograft model.
  • Figure 3 is the tumor growth curve of the mouse NCI-H292 subcutaneous and in vivo xenograft model.
  • Fig. 4 is the animal body weight change curve of the mouse NCI-H292 subcutaneous and in vivo xenograft model.
  • CTC resin 75g, 1.0mmol/g
  • Fmoc-L-citrulline 30.0g, 75.4mmol, 1.0eq
  • dichloromethane 600mL
  • N,N-diisopropylethyl Amine 58.4g, 453mmol, 6.0eq
  • Suction filtration the resin was washed twice with DMF
  • the prepared 20% piperidine/DMF solution was added to the resin mixture, the system reacted for 2 hours
  • suction filtration the resin was washed twice with DMF.
  • Step ten
  • the crude peptide P18 was dissolved in 50% MeCN/H 2 O (500 mL), slowly added TATA (purchased from WuXi AppTec, 270 mg, 0.60 mmol) under stirring at room temperature, and the addition time was more than 30 minutes. Ammonium bicarbonate was added to adjust the pH value to 8, and the reaction solution was stirred at room temperature for 12 hours. LC-MS showed that the reaction was complete. Purification by preparative HPLC (mobile phase, A: 0.075% TFA in H 2 O, B: CH 3 CN) gave a white solid HSK-P18 (94.2 mg, purity 96.3%).
  • HSK-P19, HSK-P34, HSK-P35, HSK-P36, HSK-P37, HSK-P38, HSK-P39, HSK-P40, HSK-P41, HSK-P42, HSK-P43 were synthesized respectively , HSK-P44, HSK-P45.
  • HSK-P19 The amino acid sequence is ( ⁇ -Ala)-Sar10-SEQ ID NO:1(-Hcys-P(1Nal)(D-Asp)-Hcys-M(HArg)DWSTP(Hyp)W-Hcys-), Molecular scaffolds were selected from TATB.
  • HSK-P34 The amino acid sequence is ( ⁇ -Ala)-Sar10-SEQ ID NO:4(-Hcys-P(1Nal)(D-Asp)-Cys-M(HArg)DWSTP(Hyp)W-Cys-),
  • the molecular scaffold was selected from TATA.
  • HSK-P35 The amino acid sequence is ( ⁇ -Ala)-Sar10-SEQ ID NO:3(-Cys-P(1Nal)(D-Asp)-Hcys-M(HArg)DWSTP(Hyp)W-Cys-),
  • the molecular scaffold was selected from TATA.
  • HSK-P36 The amino acid sequence is ( ⁇ -Ala)-Sar10-SEQ ID NO:2(-Cys-P(1Nal)(D-Asp)-Cys-M(HArg)DWSTP(Hyp)W-Hcys-),
  • the molecular scaffold was selected from TATA.
  • HSK-P37 The amino acid sequence is ( ⁇ -Ala)-Sar10-SEQ ID NO:7(-Hcys-P(1Nal)(D-Asp)-Hcys-M(HArg)DWSTP(Hyp)W-Cys-),
  • the molecular scaffold was selected from TATA.
  • HSK-P38 The amino acid sequence is ( ⁇ -Ala)-Sar10-SEQ ID NO:6(-Hcys-P(1Nal)(D-Asp)-Cys-M(HArg)DWSTP(Hyp)W-Hcys-),
  • the molecular scaffold was selected from TATA.
  • HSK-P39 The amino acid sequence is ( ⁇ -Ala)-Sar10-SEQ ID NO:5(-Cys-P(1Nal)(D-Asp)-Hcys-M(HArg)DWSTP(Hyp)W-Hcys-),
  • the molecular scaffold was selected from TATA.
  • HSK-P40 The amino acid sequence is ( ⁇ -Ala)-Sar10-SEQ ID NO:4(-Hcys-P(1Nal)(D-Asp)-Cys-M(HArg)DWSTP(Hyp)W-Cys-), Molecular scaffolds were selected from TATB.
  • HSK-P41 The amino acid sequence is ( ⁇ -Ala)-Sar10-SEQ ID NO:3(-Cys-P(1Nal)(D-Asp)-Hcys-M(HArg)DWSTP(Hyp)W-Cys-), Molecular scaffolds were selected from TATB.
  • HSK-P42 The amino acid sequence is ( ⁇ -Ala)-Sar10-SEQ ID NO:2(-Cys-P(1Nal)(D-Asp)-Cys-M(HArg)DWSTP(Hyp)W-Hcys-), Molecular scaffolds were selected from TATB.
  • HSK-P43 The amino acid sequence is ( ⁇ -Ala)-Sar10-SEQ ID NO:7(-Hcys-P(1Nal)(D-Asp)-Hcys-M(HArg)DWSTP(Hyp)W-Cys-), Molecular scaffolds were selected from TATB.
  • HSK-P44 The amino acid sequence is ( ⁇ -Ala)-Sar10-SEQ ID NO:6(-Hcys-P(1Nal)(D-Asp)-Cys-M(HArg)DWSTP(Hyp)W-Hcys-), Molecular scaffolds were selected from TATB.
  • HSK-P45 The amino acid sequence is ( ⁇ -Ala)-Sar10-SEQ ID NO:5(-Cys-P(1Nal)(D-Asp)-Hcys-M(HArg)DWSTP(Hyp)W-Hcys-), Molecular scaffolds were selected from TATB.
  • Step ten
  • LCMS m/z 924.00[M/6+1] + ,1108.50[M/5+1] + ,1385.60[M/4+1] + .
  • LCMS m/z 1043.7[M/5+1] + ,1304.2[M/4+1] + .
  • H292 cell culture conditions RPMI-1640+10% FBS+1% double antibody, cultured at 37°C, 5% CO 2 incubator.
  • the H292 cells in the exponential growth phase were collected and plated on 96-well culture plates, 90 ⁇ L per well, with a plating density of 500 cells/well, and cultured overnight at 37°C in a 5% CO 2 incubator.
  • 10 ⁇ L of different concentrations of compounds were added to each well so that the final concentration of DMSO in each well was 0.1%, and cultured at 37° C. in a 5% CO 2 incubator for 6 days.
  • RLU compound is the reading of drug treatment group
  • RLU control is the mean value of solvent control group.
  • Compound of the present invention is less than 100nM to the IC of NCI-H292 cell, and part is less than 50nM, more excellent less than 20nM, the results are shown in Table 4.
  • the compound of the present invention has better inhibitory activity on NCI-H292 cells.
  • Test animals male SD rats, about 220 g, 6-8 weeks old, 3 rats/compound. purchased from Chengdu Dashuo Experimental Animal Co., Ltd.
  • NC cannot be calculated
  • Compound 3 and Compound 5 have good pharmacokinetic characteristics in rats.
  • the compound of the present invention is also observed to have excellent in vivo pharmacokinetic characteristics and pharmacodynamic characteristics in animal experiments of other species.
  • NCI-H292 cells Human lung cancer NCI-H292 cells were placed in RPMI-1640 medium (supplemented with 10% fetal calf serum and 1% double antibody), and cultured at 37°C. Routine digestion with trypsin was performed twice a week for passaging. When the cell saturation is 80%-90% and the number reaches the requirement, the cells are collected, counted and inoculated. 0.1 mL (5 ⁇ 10 6 ) of NCI-H292 cells were subcutaneously inoculated into the right back of female Balb/c nude mice (from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd.), and the average tumor volume reached about 80- 120mm 3 began to group administration (recorded as Day 0).
  • the vehicle group was given 5% dimethylacetamide, 5% Solutol HS-15 and 90% normal saline solution, and the administration group was intravenously given 3 mg/kg of compound 1, compound 2, compound 4 or compound 7, and the administration frequency was every Once a week, the administration cycle is 36 days (Day 0-Day 35) or 44 days (Day 0-Day 43).
  • the tumor diameter was measured twice a week with a vernier caliper.
  • TGI (%) [1-(average tumor volume at the end of administration of a certain treatment group-average tumor volume at the beginning of administration of this treatment group)/(average tumor volume at the end of treatment of solvent control group-solvent) for the antitumor efficacy of the compound The average tumor volume at the beginning of treatment in the control group)] ⁇ 100% was evaluated.
  • Tumor growth curves and animal body weight change curves are shown in Figure 1, Figure 2, Figure 3 and Figure 4, respectively.
  • Test results after administration once a week for 36 days or 44 days, the TGI of compound 1, compound 2, compound 4 and compound 7 groups were 104%, 103%, 97% and 92% respectively; the body weight of the vehicle group decreased significantly, However, the body weight of animals in all administration groups showed an upward trend.
  • Compound 1, Compound 2, Compound 4 and Compound 7 of the present invention have good tumor growth inhibitory efficacy and good tolerance in the mouse NCI-H292 subcutaneous and in vivo xenograft model.
  • Human breast cancer MDA-MB-468 cells (derived from ATCC) and human lung cancer NCI-H322 cells (derived from ECACC) were placed in L-15 medium (supplemented with 10% fetal bovine serum) and RPMI-1640 medium (supplemented with 10% fetal bovine serum and 2 mM glutamine), cultured at 37°C, 5% CO 2 .
  • L-15 medium supplied with 10% fetal bovine serum
  • RPMI-1640 medium supplemented with 10% fetal bovine serum and 2 mM glutamine
  • Cells in the exponential growth phase were collected, and the cell suspension was adjusted to 500 cells/135 ⁇ L and 1000 cells/135 ⁇ L with medium. Add 135 ⁇ L of cell suspension to each well in a 96-well cell culture plate and incubate overnight. On the second day, different concentrations of compounds were added and cultured in an incubator for 6 days.
  • the compound of the present invention has a good inhibitory effect on MDA-MB-468 and NCI-H322 cells, and its IC50 value is less than 100nM.
  • Human lung cancer NCI-H526 cells purchased from ATCC were placed in RPMI-1640 medium (supplemented with 10% fetal bovine serum and 1% double antibody) and cultured at 37°C and 5% CO 2 . Cells in the exponential growth phase were collected, and the cell suspension was adjusted to 5000 cells/135 ⁇ L with medium. Add 135 ⁇ L of cell suspension to each well in a 96-well cell culture plate and incubate overnight. On the second day, different concentrations of compounds were added and cultured in an incubator for 6 days.
  • the compound of the present invention has weak inhibitory effect on NCI-H526 cells.

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Abstract

L'invention concerne un ligand peptidique bicyclique pour la Nectine-4 et son utilisation. La présente invention concerne spécifiquement un composé qui est un ligand peptidique ayant une affinité élevée pour des molécules d'adhésion cellulaire (Nectine-4), et concerne également un conjugué de médicament, un stéréoisomère, un sel pharmaceutiquement acceptable, un solvate, un co-cristal ou un composé deutéré associé, ou une composition pharmaceutique le contenant, et une utilisation du ligand peptidique et du conjugué de médicament dans la prévention et/ou le traitement de maladies ou d'états qui surexpriment la Nectine-4 dans un tissu malade d'un patient atteint d'une tumeur.
PCT/CN2022/126245 2021-10-19 2022-10-19 Ligand peptidique bicyclique pour nectine-4 et son utilisation WO2023066314A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112566651A (zh) * 2018-06-22 2021-03-26 拜斯科技术开发有限公司 特异于结合素-4的双环肽配体
WO2021074622A1 (fr) * 2019-10-15 2021-04-22 Bicycletx Limited Conjugués de médicament à ligand peptidique bicyclique

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CN112566651A (zh) * 2018-06-22 2021-03-26 拜斯科技术开发有限公司 特异于结合素-4的双环肽配体
CN112601539A (zh) * 2018-06-22 2021-04-02 拜斯科技术开发有限公司 特异于结合素-4的双环肽配体
WO2021074622A1 (fr) * 2019-10-15 2021-04-22 Bicycletx Limited Conjugués de médicament à ligand peptidique bicyclique

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RIGBY, M.: "BT8009: A bicyclic peptide toxin conjugate targeting Nectin-4(PVRL4) displays efficacy in preclinical tumour models.", AACR ANNUAL MEETING 2019 ATLANTA, 31 December 2019 (2019-12-31), XP009545791 *
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