WO2023088236A1 - Ligand peptidique bicyclique de mt1-mmp et son conjugué - Google Patents

Ligand peptidique bicyclique de mt1-mmp et son conjugué Download PDF

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WO2023088236A1
WO2023088236A1 PCT/CN2022/131909 CN2022131909W WO2023088236A1 WO 2023088236 A1 WO2023088236 A1 WO 2023088236A1 CN 2022131909 W CN2022131909 W CN 2022131909W WO 2023088236 A1 WO2023088236 A1 WO 2023088236A1
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ala
hcys
asp
glu
cys
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Chinese (zh)
Inventor
李瑶
陈雷
黄海涛
王浩东
唐平明
余彦
张晨
严庞科
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Haisco Pharmaceutical Group Co Ltd
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Haisco Pharmaceutical Group Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • 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

Definitions

  • the present invention relates to a compound containing a polypeptide structure with high affinity for membrane-type matrix metalloproteinase 1 (MT1-MMP) and a polypeptide drug conjugate conjugated to one or more toxin molecules, and the compound and drug conjugate
  • MT1-MMP membrane-type matrix metalloproteinase 1
  • the related use of the compound including the use of preparing a pharmaceutical composition and the use of a medicine for preventing and/or treating a disease overexpressing MT1-MMP.
  • Matrix metalloproteinases are a family of zinc-dependent endoproteases that can degrade most components in the extracellular matrix (extracellular matrix, ECM).
  • ECM extracellular matrix
  • a total of 25 members of the matrix metalloproteinase family have been discovered so far, and 24 species exist in mammals, which are related to various physiological and pathological conditions.
  • Sato et al. identified the first membrane-type matrix metalloproteinase, now called MT1-MMP, and found that it is an agonist of the cell surface MMP-2 zymogen, and it is also a membrane-type matrix metalloproteinase that has been studied more. Protease.
  • Membrane-type matrix metalloproteinase-1 (MT1-MMP) is an important member of the matrix metalloproteinase family, and its encoded protein has a relative molecular mass of 66kDa, which plays an important role in the degradation of the extracellular matrix and is highly Participating in the process of cell invasion to tissue and the formation of epithelial cell polarity, it is considered to be the enzyme most closely related to tumor invasion in the MMP family.
  • MT1-MMP is mainly expressed in fibroblasts, smooth muscle cells and endothelial cells, but it is highly expressed in tumor cells and adjacent stromal cells of most human malignant tumors such as gastric cancer, colon cancer and liver cancer.
  • MT1-MMP is closely related to the poor prognosis of individuals with neuroblastoma, small cell lung cancer, and bladder cancer.
  • the low expression of MT1-MMP is considered to be a good survival indicator in patients with advanced colorectal cancer.
  • MMPs overexpressed proteases
  • MMPs can be used as marker molecular signals for diagnosing tumor cell invasion and migration.
  • MMPs as targets to treat diseases has become a new research hotspot.
  • the research on the function of MT1-MMP at the enzymatic molecular level is relatively thorough, and there is evidence that it can promote the occurrence and development of diseases such as tumors.
  • MT1-MMP is located on the cell surface and is highly expressed in a variety of tumor cells, making MT1-MMP an ideal target for tumor therapy.
  • different types of artificially synthesized MMP inhibitors are used to treat tumors, but the clinical effect is not satisfactory.
  • inhibitors have broad-spectrum specificity, not only inhibiting target enzymes, but also inhibiting some Beneficial enzymes. Therefore, it is of great significance to screen ligands that can specifically bind to MT1-MMP and use them as targeted drug delivery carriers.
  • the present invention firstly provides a compound specific to MT1-MMP, 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 also provides a pharmaceutical composition, and in their Use in medicines for the prevention and/or treatment of diseases overexpressing MT1-MMP.
  • the compounds, drug conjugates and drug compositions of the present invention have high affinity to targets, good selectivity and high stability.
  • the present invention relates to a compound comprising a polypeptide structure and an aromatic molecular scaffold, the polypeptide structure comprising at least three residues independently selected from Cys and Hcys, and at least one of the three residues is an Hcys residue, the The three residues are separated by two amino acid sequences, and the Cys or Hcys residues of the polypeptide structure are connected with the molecular scaffold through a thioether bond, thereby forming two polypeptide rings on the molecular scaffold.
  • the compound comprises a polypeptide structure and an aromatic molecular scaffold, the polypeptide structure comprising at least three residues independently selected from Cys and Hcys, and one of the three residues is a Hcys residue , the three residues are separated by two amino acid sequences, and the Cys or Hcys residues of the polypeptide structure are connected to the molecular scaffold through a thioether bond, thereby forming two polypeptide rings on the molecular scaffold.
  • the compound comprises a polypeptide structure and an aromatic molecular scaffold, the polypeptide structure comprising at least three residues independently selected from Cys and Hcys, and two of the three residues are Hcys residues The three residues are separated by two amino acid sequences, and the Cys or Hcys residues of the polypeptide structure are connected to the molecular scaffold through a thioether bond, thereby forming two polypeptide rings on the molecular scaffold.
  • the aromatic molecular scaffold is selected from TBMB.
  • the compound comprises a polypeptide structure and an aromatic molecular scaffold, the polypeptide structure comprising at least three residues independently selected from Cys and Hcys, and one of the three residues is a Hcys residue , the three residues are separated by two amino acid sequences, and the Cys or Hcys residues of the polypeptide structure are connected to the molecular scaffold through a thioether bond, thereby forming two polypeptide rings on the molecular scaffold, so
  • the molecular scaffold described above is selected from TBMB.
  • the compound comprises a polypeptide structure and an aromatic molecular scaffold, the polypeptide structure comprising at least three residues independently selected from Cys and Hcys, and two of the three residues are Hcys residues base, the three residues are separated by two amino acid sequences, and the Cys or Hcys residues of the polypeptide structure are connected to the molecular scaffold through a thioether bond, thereby forming two polypeptide rings on the molecular scaffold,
  • the molecular scaffold is selected from TBMB.
  • polypeptide structure of the compound comprises an amino acid sequence selected from:
  • a 1 and A 2 represent amino acid residues among Xa 1 , Xa 2 , and Xa 3 , and each of A 1 and A 2 independently comprises 5 or 6 amino acid residues; in some specific embodiments, A 1 , A The amino acid residue that A2 comprises is optionally selected from Hyp, D-Ala, Glu, Leu, 1-Nal, Val, Asn, Pro, Leu, His, D-Asp, Asp, tBu-Gly, Trp, hArg , Ser, Thr, Tyr, Val, Ile and Gly, etc.;
  • Xa 1 , Xa 2 , and Xa 3 are independently Cys or Hcys residues, and at least one of them is a Hcys residue, and the aromatic molecular scaffold forms thioether bonds with Xa 1 , Xa 2 , and Xa 3 of the polypeptide, respectively Thus two polypeptide loops are formed on the molecular scaffold.
  • polypeptide structure comprises the amino acid sequence shown below:
  • polypeptide structure comprises the amino acid sequence shown in any one of SEQ ID NO:1 ⁇ SEQ ID NO:7:
  • Hcys-(D-Ala)-Asn-Glu-(1-Nal)-(D-Ala)-Hcys-Glu-Asp-Phe-Tyr-Asp-(tBu-Gly)-Hcys (SEQ ID NO: 1) ;
  • 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 having one of the following structures, optionally containing additional amino acid sequences at the N-terminus and/or C-terminus of the following structures:
  • the -SH group on the Xa 1 , Xa 2 or Xa 3 residue is covalently bonded to the molecular scaffold to form a thioether bond. Therefore, when Xa 1 , Xa 2 or Xa 3 is Cys, correspondingly, n 1 , n 2 or n 3 is 1;
  • n 1 , n 2 or n 3 is 2.
  • the bicyclic peptide of formula I-1 or I wherein:
  • Xa 1 , Xa 2 , Xa 3 are Hcys, n 1 , n 2 , n 3 are 2; or
  • Xa 1 and Xa 3 are Hcys, Xa 2 is Cys, n 1 and n 3 are 2, and n 2 is 1; or
  • Xa 1 and Xa 2 are Cys, Xa 3 is Hcys, n 1 and n 2 are 1, and n 3 is 2.
  • the compound is selected from one of the following structures:
  • the compound containing 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 MT1-MMP, and is Peptide ligand specific to MT1-MMP; has long plasma half-life, good pharmacokinetic and pharmacodynamic properties.
  • the present invention also provides the use of the compound as a ligand of MT1-MMP in screening and/or preparing drugs.
  • 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 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 one or more of the following group: cisplatin, carboplatin, oxaliplatin, nitrogen mustard, cyclophosphamide, chlorambucil, isocycline Phosphoramide, azathioprine, mercaptopurine, pyrimidine analogues, vincristine, vinblastine, vinorelbine, vindesine, etoposide, teniposide, paclitaxel, camptothecin, 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 derivative
  • the cytotoxic agent is at least one selected from maytansinoids, monomethyl auristatin, and camptothecin derivatives.
  • the cytotoxic agent is selected from the group consisting of maytansine DM1 (DM1), maytansine DM4 (DM4), monomethyl auristatin E (MMAE), 7-ethyl-10-hydroxyl At least one of the resins (SN38).
  • the linker is a peptide linker, a disulfide linker, or a pH-dependent linker; these linkers are cleavable under certain conditions to release the effector molecule.
  • the disulfide linker is selected from DMDS, MDS, DSDM, NDMDS or the structure of formula II:
  • 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 linker is mainly used to connect the toxic agent and the peptide ligand, and to release the toxic substance by cleavage under specific conditions.
  • the linker can be appropriately modified, such as in the Peptide ligands or effectors connect some groups to increase the chain length, and increase group modification around the cleavage bond to control the hindrance of the cleavage bond.
  • the linker of the present invention includes linker derivatives modified based on the above.
  • 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.
  • the linker is -PABC-Cit-Val-glutaryl- or -PABC-cyclobutyl-Ala-Cit- ⁇ Ala-, where PABC stands for p-aminobenzylcarbamate .
  • the linker is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl linker
  • k is selected from any integer of 1-20.
  • the linker is In some specific embodiments, the linker is In some specific embodiments, the linker is In some specific embodiments, the linker is In respective embodiments, 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; in some embodiments, k is selected from 2.
  • the drug conjugate has the structure of Formula III, Formula IV, Formula V, or Formula VI:
  • 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;
  • k is independently any integer of 1-10;
  • Xa 1 , Xa 2 , and Xa 3 are independently Cys or Hcys residues, and at least one of them is a Hcys residue;
  • n 1 , n 2 or n 3 is 1;
  • n 1 , n 2 or n 3 is 2.
  • the drug conjugate or a pharmaceutically acceptable salt thereof wherein:
  • R 1 , R 2 , R 3 and R 4 are independently selected from H or methyl;
  • p and q are independently 1 or 2;
  • k is independently any integer from 1 to 5;
  • Xa 1 , Xa 2 , Xa 3 are Hcys, n 1 , n 2 , n 3 are 2; or
  • Xa 1 and Xa 3 are Hcys, Xa 2 is Cys, n 1 and n 3 are 2, and n 2 is 1; or
  • Xa 1 and Xa 2 are Cys, Xa 3 is Hcys, n 1 and n 2 are 1, and n 3 is 2.
  • a drug conjugate or a pharmaceutically acceptable salt thereof is selected from one of the following structures:
  • the present invention also relates to a pharmaceutical composition, which contains 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 contains 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 composition thereof in the preparation of preventing and/or treating overexpression of MT1 - Use of MMPs in medicine for diseases.
  • the disease overexpressing MT1-MMP is selected from at least one of the following diseases: neuroblastoma, small cell lung cancer, bladder cancer, gastric cancer, colon cancer, liver 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 peptide compound described in the present invention or the conjugate described in the present invention or its A pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier and/or excipient.
  • 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 peptide compound of the present invention or the aforementioned conjugate of the present invention or its For pharmaceutically acceptable salts, the therapeutically effective dose is preferably 1-1500 mg, and the disease is preferably at least one of neuroblastoma, small cell lung cancer, bladder cancer, gastric cancer, colon cancer, and liver cancer.
  • the present invention also provides a composition or pharmaceutical preparation, which contains the aforementioned peptide compound, conjugate or pharmaceutically acceptable salt thereof of the present invention, 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 aforementioned peptide compound, conjugate or pharmaceutically acceptable salt thereof of the present invention, and pharmaceutically acceptable carriers and/or excipients .
  • the present invention also provides the use of the aforementioned peptide compounds, conjugates or pharmaceutically acceptable salts thereof in the preparation of drugs for the prevention and treatment of diseases or disorders in which MT1-MMP is overexpressed in diseased tissues of tumor individuals .
  • the disease or disease overexpressing MT1-MMP is preferably at least one of neuroblastoma, small cell lung cancer, bladder cancer, gastric cancer, colon cancer, and liver cancer.
  • 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 aforementioned peptide compounds, conjugates or pharmaceutically acceptable ones shown in the present invention salt, the disease is preferably at least one of neuroblastoma, small cell lung cancer, bladder cancer, gastric cancer, colon cancer, and liver cancer, and preferably the therapeutically effective dose 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 ,
  • 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 . , 1100mg , 1200mg, 1300mg, 1400mg, 1500mg of the peptide compound, conjugate or pharmaceutically acceptable salt thereof of the present invention.
  • 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 of the present invention, a conjugate, or a pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier and/or excipient, the therapeutically effective dose is preferably 1-1500 mg, and the disease is preferably neuroblastoma, small cell lung cancer, bladder cancer, gastric cancer, colon cancer, liver cancer at least one.
  • the present invention provides a method for treating a disease in a mammal or a human.
  • the method comprises administering the peptide compound, the conjugate or a pharmaceutically acceptable salt thereof of the present invention, and a pharmaceutically Acceptable carriers and/or excipients 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 , 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 , 10mg/day, 20mg/day, 25mg/day, 50mg/day, 75mg/day, 100mg/day, 10mg/day
  • 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 its stereoisomer or pharmaceutically acceptable salt is the same as that in the above pharmaceutical composition.
  • Preparation specification refers to the weight of the main drug contained in each tube, tablet or other unit preparation.
  • the peptides 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:
  • a peptide ligand refers to a compound containing an amino acid sequence (peptide structure) formed by covalently binding a peptide to a molecular scaffold.
  • it can be used as the ligand of membrane-type matrix metalloproteinase-1 (MT1-MMP).
  • the peptides forming such compounds contain two or more reactive groups (i.e. cysteine residues or homocysteine residues) capable of forming covalent bonds (e.g. thioether bonds) with the scaffold , and the opposing sequence between the reactive groups, called the loop sequence, is called a loop sequence because when the peptide binds to the scaffold, it forms a loop.
  • the peptide comprises at least three cysteine residues or homocysteine residues (Cys residues or Hcys residues), which form two loops on the scaffold.
  • Molecular scaffolds include aromatic molecular scaffolds.
  • An aromatic molecular scaffold refers to any molecular scaffold as defined herein comprising an aromatic carbocyclic or aromatic heterocyclic ring system. Examples of suitable 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.
  • Polypeptide refers to a compound formed by three or more amino acid molecules linked 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.
  • cytotoxic agents including alkylating agents, antimetabolites, plant alkaloids, terpenoids, podophyllotoxins and their derivatives, taxanes and their derivatives, topoisomerases Inhibitors, antitumor antibiotics, etc.
  • cisplatin carboplatin, oxaliplatin, mechlorethamine, cyclophosphamide, chlorambucil, ifosfamide, azathioprine, mercaptopurine, pyrimidine analogs, vincristine, vinca Alkaline, vinorelbine, vindesine, etoposide, teniposide, paclitaxel, camptothecin, irinotecan, topotecan, 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 substances, mitomycin C, cynistatin, maytansine and its derivatives, auristatin and its derivatives.
  • Derivatives refer to products derived from the substitution of hydrogen atoms or atomic groups in a compound by other atoms or atomic groups.
  • Trp tryptophan
  • Maytansinoids such as DM1 and DM4, are cytotoxic agents, which are thiol-containing derivatives of maytansine.
  • DM1 has the following structure:
  • DM4 has the following structure:
  • MMAE Monomethyl auristatin E
  • monomethyl auristatin E is a synthetic antineoplastic agent and has the following structure:
  • the carbon, hydrogen, oxygen, sulfur, nitrogen or halogens 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
  • HBTU Benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate
  • 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 P22 was dissolved in 50% MeCN/H 2 O (500 mL), and TBMB (purchased from WuXi AppTec, 270 mg, 0.60 mmol) was slowly added under stirring at room temperature for 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-P22 (42.1 mg, purity 97.3%).
  • HSK-P46, HSK-P47, HSK-P48, HSK-P49, HSK-P50, HSK-P51 were synthesized respectively.
  • HSK-P22 The amino acid sequence is ( ⁇ -Ala)-Sar10-Ala-SEQ ID NO: 1(Hcys-(D-Ala)-Asn-Glu-(1-Nal)-(D-Ala)-Hcys-Glu -Asp-Phe-Tyr-Asp-(tBu-Gly)-Hcys) (i.e. SEQ ID NO: 8), the molecular scaffold is selected from TBMB.
  • HSK-P46 The amino acid sequence is ( ⁇ -Ala)-Sar10-Ala-SEQ ID NO: 4(Hcys-(D-Ala)-Asn-Glu-(1-Nal)-(D-Ala)-Hcys-Glu -Asp-Phe-Tyr-Asp-(tBu-Gly)-cys) (i.e. SEQ ID NO: 11), the molecular scaffold is selected from TBMB.
  • HSK-P47 The amino acid sequence is ( ⁇ -Ala)-Sar10-Ala-SEQ ID NO: 3(Hcys-(D-Ala)-Asn-Glu-(1-Nal)-(D-Ala)-Cys-Glu -Asp-Phe-Tyr-Asp-(tBu-Gly)-Hcys) (i.e. SEQ ID NO: 10), the molecular scaffold is selected from TBMB.
  • HSK-P48 The amino acid sequence is ( ⁇ -Ala)-Sar10-Ala-SEQ ID NO: 2(Cys-(D-Ala)-Asn-Glu-(1-Nal)-(D-Ala)-Hcys-Glu -Asp-Phe-Tyr-Asp-(tBu-Gly)-Hcys) (i.e. SEQ ID NO:9), the molecular scaffold is selected from TBMB.
  • HSK-P49 The amino acid sequence is ( ⁇ -Ala)-Sar10-Ala-SEQ ID NO: 7(Hcys-(D-Ala)-Asn-Glu-(1-Nal)-(D-Ala)-Cys-Glu -Asp-Phe-Tyr-Asp-(tBu-Gly)-Cys) (i.e. SEQ ID NO: 14), the molecular scaffold is selected from TBMB.
  • HSK-P50 The amino acid sequence is ( ⁇ -Ala)-Sar10-Ala-SEQ ID NO: 6(Cys-(D-Ala)-Asn-Glu-(1-Nal)-(D-Ala)-Hcys-Glu -Asp-Phe-Tyr-Asp-(tBu-Gly)-Cys) (i.e. SEQ ID NO: 13), the molecular scaffold is selected from TBMB.
  • HSK-P51 The amino acid sequence is ( ⁇ -Ala)-Sar10-Ala-SEQ ID NO: 5(Cys-(D-Ala)-Asn-Glu-(1-Nal)-(D-Ala)-Cys-Glu -Asp-Phe-Tyr-Asp-(tBu-Gly)-Hcys) (i.e. SEQ ID NO: 12), the molecular scaffold is selected from TBMB.
  • Step ten
  • HT-1080 cell culture conditions EMEM+10% FBS+1% double antibody, cultured at 37°C, 5% CO 2 incubator.
  • HT-1080 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 3 days.
  • Inhibition% (1-(RLU compound/RLU control) ⁇ 100% Formula (1)
  • the compound of the present invention has higher inhibitory activity.
  • Human multiple myeloma MOLP8 cells purchased from DSMZ were placed in RPMI-1640 complete medium (supplemented with 20% fetal bovine serum) and cultured at 37°C and 5% CO 2 . Cells in the exponential growth phase were collected, and the cell suspension was adjusted to 8000 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 5 days.
  • 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
  • the reference compound is BT17BDC-18 of WO2016067035A1, the structural formula is
  • Test animals male balb/c mice, 20-25g, 9/compound. purchased from Chengdu Dashuo Experimental Animal Co., Ltd.
  • Test animals male cynomolgus monkeys, 3-5kg, 3-6 years old, 3 animals/compound. purchased from Suzhou Xishan Biotechnology Co., Ltd.
  • Test method On the test day, 3 monkeys were randomly divided into groups according to body weight. One day before the administration, fasting without water for 14-18 hours, and giving food 4 hours after the administration.
  • 1.0 mL of blood was collected from the veins of the extremities, and placed in EDTAK2 centrifuge tubes. Centrifuge at 5000 rpm for 10 min at 4°C to collect plasma. The time points of blood collection in the vein group were: 0, 2, 5, 15, 30min, 1, 2, 4, 6, 8, 24h. Before analysis and detection, all samples were stored at -80°C, and the samples were quantitatively analyzed by LC-MS/MS.
  • the compounds of the present invention have good pharmacokinetic characteristics in monkeys.
  • the compound of the present invention has good pharmacokinetic characteristics in dogs.

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Abstract

L'invention concerne un peptide ayant une affinité élevée vis-à-vis de la métalloprotéinase 1 matricielle de type membranaire (MT1-MMP), un conjugué de médicaments, un stéréoisomère, un sel, un solvate, un co-cristal ou un produit deutéré pharmaceutiquement acceptables de celui-ci, ou une composition pharmaceutique le contenant, et une utilisation du ligand peptidique et des conjugués de médicaments dans la prévention et le traitement de maladies ou de troubles dans lesquels MT1-MMP est surexprimé dans un tissu malade d'individus atteints de tumeurs.
PCT/CN2022/131909 2021-11-16 2022-11-15 Ligand peptidique bicyclique de mt1-mmp et son conjugué Ceased WO2023088236A1 (fr)

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Citations (6)

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Publication number Priority date Publication date Assignee Title
CN107148425A (zh) * 2014-10-29 2017-09-08 拜斯科医疗有限公司 对mt1‑mmp特异性的双环肽配体
CN109414510A (zh) * 2016-05-04 2019-03-01 拜斯科阿迪有限公司 Mt1-mmp特异性双环肽-毒素缀合物
CN110506049A (zh) * 2016-12-23 2019-11-26 拜斯科技术开发有限公司 用于结合mt1-mmp的肽配体
CN113474047A (zh) * 2018-12-13 2021-10-01 拜斯科技术开发有限公司 Mt1-mmp特异性的双环肽配体
CN113507962A (zh) * 2018-12-13 2021-10-15 拜斯科技术开发有限公司 Mt1-mmp特异性的双环肽配体
CN113518648A (zh) * 2018-12-13 2021-10-19 拜斯科阿迪有限公司 Mt1-mmp特异性的双环肽配体

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CN107148425A (zh) * 2014-10-29 2017-09-08 拜斯科医疗有限公司 对mt1‑mmp特异性的双环肽配体
CN109414510A (zh) * 2016-05-04 2019-03-01 拜斯科阿迪有限公司 Mt1-mmp特异性双环肽-毒素缀合物
CN110506049A (zh) * 2016-12-23 2019-11-26 拜斯科技术开发有限公司 用于结合mt1-mmp的肽配体
CN113474047A (zh) * 2018-12-13 2021-10-01 拜斯科技术开发有限公司 Mt1-mmp特异性的双环肽配体
CN113507962A (zh) * 2018-12-13 2021-10-15 拜斯科技术开发有限公司 Mt1-mmp特异性的双环肽配体
CN113518648A (zh) * 2018-12-13 2021-10-19 拜斯科阿迪有限公司 Mt1-mmp特异性的双环肽配体

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EDER, M ET AL.: "Bicyclic Peptides as a New Modality for Imaging and Targeting of Proteins Overexpressed by Tumors", CANCER RESEARCH, vol. 79, no. 4, 15 February 2019 (2019-02-15), pages 841 - 852, XP055669350, DOI: 10.1158/0008-5472.CAN-18-0238 *

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