WO2020216319A1 - Adam9抑制剂作为免疫调节剂的用途 - Google Patents

Adam9抑制剂作为免疫调节剂的用途 Download PDF

Info

Publication number
WO2020216319A1
WO2020216319A1 PCT/CN2020/086642 CN2020086642W WO2020216319A1 WO 2020216319 A1 WO2020216319 A1 WO 2020216319A1 CN 2020086642 W CN2020086642 W CN 2020086642W WO 2020216319 A1 WO2020216319 A1 WO 2020216319A1
Authority
WO
WIPO (PCT)
Prior art keywords
adam9
compound
cells
tumor
inhibitor according
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CN2020/086642
Other languages
English (en)
French (fr)
Inventor
佘玉萍
杨颛丞
刘璟霈
黄裕锴
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
China Medical University Taiwan
Original Assignee
China Medical University Taiwan
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by China Medical University Taiwan filed Critical China Medical University Taiwan
Priority to US17/605,857 priority Critical patent/US20220202783A1/en
Priority to CN202080031194.5A priority patent/CN114173778B/zh
Priority to EP20796014.7A priority patent/EP3960171B1/en
Publication of WO2020216319A1 publication Critical patent/WO2020216319A1/zh
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators

Definitions

  • the present invention relates to the use of an ADAM9 inhibitor, especially the use of an ADAM9 inhibitor as an immunomodulator.
  • Cancer also known as malignant tumor, is abnormal cell proliferation, and these proliferating cells may invade other parts of the body. It is a disease caused by abnormal mechanisms that control cell division and proliferation.
  • the number of people suffering from cancer in the world is increasing. Cancer is one of the top ten causes of death in China, and it has been the top ten cause of death for 27 consecutive years.
  • the occurrence of cancer metastasis is the main cause of high cancer deaths.
  • the prognosis of brain metastasis from lung cancer is extremely poor. Even if patients with early lung cancer can surgically remove the tumor, 25% will develop remote cancer metastasis.
  • common anticancer drugs can be used to inhibit the growth of cancer cells, they are still limited in preventing cancer recurrence.
  • the role of molecules that promote metastasis can be regarded as a forward-looking approach.
  • ADAM9 Disintegrin and metalloproteinase domain-containing protein 9 (ADAM9) is overexpressed in many tumors, such as pancreatic cancer, breast cancer, prostate cancer and lung cancer, and ADAM9 high expression level is associated with cancer Poor patient prognosis is related and can be used as a predictive marker. Because ADAM9 expression can help tumor cells adapt to unfavorable environments, ADAM9 is considered to promote tumor development and is considered to be a better therapeutic target than other cancer-related metalloproteinases.
  • ADAM9 participates in tumorigenesis due to its ability to cut and release many molecules involved in cancer progression, and participates in tumorigenesis due to its ability to cut and release many molecules involved in cancer progression, and ADAM9 secreted by stromal cells around the tumor can be Promote tumor development through neovascularization.
  • One aspect of the present invention is to provide a use of an ADAM9 inhibitor, which is applied to the preparation of immunomodulators.
  • the immunomodulator can be used to enhance the effectiveness of cancer immunotherapy.
  • the subject of administration of the cancer immunotherapy may be a patient with a weakened immune function.
  • the immunomodulator can be used to stimulate the infiltration of immune cells into tumors.
  • the immune cells may be T cells, natural killer cells, macrophages, neutrophils, dendritic cells or suppressor cells derived from bone marrow.
  • the immunomodulator can be used to change the types of chemokines in the tumor microenvironment.
  • the immunomodulator can be used to treat tumors resistant to immunotherapy.
  • the immunotherapy-resistant tumor may be resistant to checkpoint inhibitors, adoptive cell transfer, therapeutic antibodies, therapeutic vaccines, cytokines, immune cell therapy, or a combination thereof.
  • the checkpoint inhibitor can be an anti-CTLA-4 antibody, an anti-PDL1 antibody or an anti-PD-1 antibody.
  • the immunomodulator can be formulated together with a checkpoint inhibitor.
  • the checkpoint inhibitor may be an anti-CTLA-4 antibody, an anti-PDL1 antibody or an anti-PD-1 antibody.
  • the ADAM9 inhibitor may be a compound of formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof,
  • R is a C 1 -C 18 hydrocarbon group containing 0 to 3 heteroatoms independently selected from nitrogen, sulfur and oxygen, or is substituted with a heteroatom selected from nitrogen, sulfur and oxygen, containing 0 to 3 independent
  • R can be NHR 1 and R 1 is 2-thiazol-4-yl-ethyl-isoindoline-1,3-dione.
  • the ADAM9 inhibitor of the embodiment of the present invention can change the distribution of immune cells in the tumor and increase the infiltration of immune cells, thereby having an immune regulation function, and is suitable for preparing immunomodulators.
  • Figure 1A and Figure 1B are graphs showing the analysis results of the compound of formula (I) inhibiting ADAM9 activity
  • Figure 2A, Figure 2B, Figure 2C, Figure 2D, Figure 2E, Figure 2F, Figure 2G and Figure 2H are the results of the analysis of the characteristics of the compound of formula (I) in the in vitro test;
  • Figure 3 is the result of analysis of the effect of excluding ADAM9 on tumor growth
  • Figure 4A, Figure 4B, Figure 4C and Figure 4D are the results of RNA analysis of ADAM9, CD4, CD8 and IFN- ⁇ in tumor tissues after ADAM9 has been removed;
  • Figures 5A and 5B are graphs showing the analysis results of the effect of removing ADAM9 on lung metastatic tumor growth and immune cell infiltration;
  • Fig. 6 is a graph showing the analysis result of apoptosis rate of target cells and effector cells after 24 hours of co-cultivation
  • Figure 7A is a graph showing the analysis results of the anti-tumor effects of ADAM9 inhibitors
  • Figure 7B is a flow chart of ADAM9 inhibitors used in the treatment of an animal model of syngeneic orthotopic breast tumors
  • Figures 8A and 8B are graphs showing the analysis results of the effects of ADAM9 inhibitors on immune cell infiltration
  • Figure 9 is a graph showing the analysis results of co-processing ADAM9 inhibitors and checkpoint inhibitors.
  • Figure 10A, Figure 10B and Figure 10C are graphs showing the analysis results of ADAM9 inhibitor stimulating tumor cells to secrete cytokines.
  • the present invention provides a use of an ADAM9 inhibitor, which is applied to prepare an immunomodulator.
  • the immunomodulator can be used to stimulate the infiltration of immune cells into tumors.
  • the immune cells may be T cells, natural killer cells, macrophages, neutrophils, dendritic cells or suppressor cells derived from bone marrow.
  • the immunomodulator can be used to change the types of chemokines in the tumor microenvironment or to enhance the effectiveness of cancer immunotherapy.
  • the subject of administration of the cancer immunotherapy may be a patient with a weakened immune function.
  • the present invention also provides a use of an ADAM9 inhibitor, which is applied to the preparation of an immunomodulator.
  • the immunomodulator can be used to treat tumors resistant to immunotherapy.
  • the immunotherapy-resistant tumor may be resistant to checkpoint inhibitors, adoptive cell transfer, therapeutic antibodies, therapeutic vaccines, cytokines, immune cell therapy, or a combination thereof.
  • the checkpoint inhibitor may be a molecule used to inhibit immune checkpoint protein in the activation of immune cells, preferably, it may be an anti-CTLA-4 antibody, an anti-PDL1 antibody or an anti-PD-1 antibody.
  • the aforementioned ADAM9 inhibitors can also be used with checkpoint inhibitors to enhance the effectiveness of cancer immunotherapy.
  • the aforementioned ADAM9 inhibitors can also be used in combination with chemotherapeutics and/or checkpoint inhibitors to serve as pharmaceutical compositions for the treatment of cancer.
  • the ADAM9 inhibitor may be a compound of formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof,
  • R is a C 1 -C 18 hydrocarbon group containing 0 to 3 heteroatoms independently selected from nitrogen, sulfur and oxygen, or is substituted with a heteroatom selected from nitrogen, sulfur and oxygen, containing 0 to 3 independent
  • R can be a secondary amine, amide, NHR 1 , NHCOR 2 or a structure as shown in formula (i):
  • R 1 may be an aryl group containing 0 to 3 heteroatoms independently selected from nitrogen, sulfur and oxygen.
  • R 1 can be 2-thiazol-4-yl-ethyl-isoindoline-1,3-dione.
  • R 2 may be a phenyl or benzoheterocyclic group containing 0 to 3 heteroatoms independently selected from nitrogen, sulfur, and oxygen.
  • R 2 may be benzothiophene.
  • R 3 may be an optionally substituted phenyl, benzoheterocyclic group, or heterocyclic group containing 0 to 3 heteroatoms independently selected from nitrogen, sulfur, and oxygen.
  • a and “an” in this article and in this specification mean that the grammatical object in the article is one or more (ie at least one).
  • the category is an abbreviation of all members included in the category, for example, C 1 -C 3 alkyl is an abbreviation for all C 1 -C 3 alkyls, for example, C 1 -C 3 alkyl Contains methyl, ethyl, propyl and their isomers.
  • alkenyl groups can be selected from but not limited to vinyl or vinyl, prop-1-enyl, prop-2-enyl, 2-methylprop-1-enyl, but-1-enyl, but- 2-alkenyl, but-3-enyl, but-1,3-dienyl, 2-methylbut-1,3-diene, hex-1-enyl, hex-2-enyl, hexyl -3-alkenyl, hex-4-enyl and hexa-1,3-diene groups.
  • the "aryl” mentioned in this specification refers to a group selected from the group consisting of 5- and 6-membered carbocyclic aromatic rings, such as phenyl, bicyclic ring systems, and tricyclic ring systems.
  • the bicyclic ring system may be a 7-12 membered bicyclic ring system, wherein at least one ring is a carbocyclic ring and an aromatic ring, which is selected from but not limited to naphthalene, indane and 1,2,3,4-tetrahydroquinoline .
  • the tricyclic ring system may be a 10-15 membered tricyclic ring system, in which at least one ring is a carbocyclic ring and an aromatic ring, such as fluorene.
  • the aryl group is selected from 5- and 6-membered carbocyclic aryl groups fused with 5- to 7-membered cycloalkyl or heterocycle optionally containing at least one heteroatom selected from nitrogen, oxygen, and sulfur. ring.
  • the point of attachment is on the carbocyclic aromatic ring.
  • the point of attachment can be on the carbocyclic aromatic ring or cycloalkyl.
  • a divalent group formed from a substituted benzene derivative and having a free valence on a ring atom is called a substituted phenylene group.
  • a divalent group derived from a monovalent polycyclic hydrocarbon group whose name ends with "-idene” by removing a hydrogen atom from a carbon atom with a free valence is added by adding "- subunit (-yl)" to Named from the name of the corresponding monovalent group, for example, a naphthyl group with two points of attachment is called a naphthylene group.
  • the aryl group does not include a heteroaryl group or overlaps with a heteroaryl group, and is defined separately below in this specification. Therefore, if one or more carbocyclic aromatic rings are fused with a heterocyclic aromatic ring, the resulting ring system is a heteroaryl group instead of an aryl group as defined in this specification.
  • heteroaryl group refers to a group selected from the following: 5- to 7-membered aromatic monocyclic ring, containing 1, 2, 3 or 4 heteroatoms selected from nitrogen, oxygen and sulfur, The remaining ring atoms are carbon; an 8- to 12-membered bicyclic ring containing 1, 2, 3, or 4 heteroatoms selected from nitrogen, oxygen and sulfur, the remaining ring atoms are carbon, and at least one of the rings is aromatic and At least one heteroatom is present in the aromatic ring.
  • a heteroaryl group includes a 5- to 7-membered heterocyclic aromatic ring fused to a 5- to 7-membered cycloalkyl ring.
  • the aforementioned fused bicyclic heteroaryl ring system in which only one ring contains at least one heteroatom, and the point of attachment can be on the heteroaromatic ring or the cycloalkyl ring.
  • the heteroatoms are not adjacent to each other.
  • the total number of sulfur and oxygen atoms in the heteroaryl group is not more than two, and in other embodiments, the total number of sulfur and oxygen atoms in the aromatic heterocycle is not more than one.
  • heteroaryl groups include, but are not limited to (numbering starting from the linking position of priority 1) pyridyl (such as 2-pyridyl, 3-pyridyl or 4-pyridyl), quinolinyl, pyrazinyl, 2 ,4-pyrimidinyl, 3,5-pyrimidinyl, 2,4-imidazolyl, imidazopyridyl, isoxazolyl, oxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, tetrazolyl, Thienyl, triazinyl, benzothienyl, furyl, benzofuranyl, benzimidazolyl, indolyl, isoindolyl, indoline, phthalazinyl, pyrazinyl, pyridazine Group, pyrrolyl, triazolyl, quinolinyl, isoquinolinyl, pyrazolyl,
  • Compounds may contain asymmetric centers, so they can exist as enantiomers. When a compound has two or more asymmetric centers, it may additionally exist as diastereomers.
  • Spiegelmers and diastereomers belong to a broader category of stereoisomers. All possible stereoisomers include, for example, substantially pure separable enantiomers, racemic mixtures thereof, and mixtures of diastereomers. All stereoisomers and/or pharmaceutically acceptable salts of the compounds are included where applicable. Unless otherwise stated, the isomers mentioned apply to any possible isomers. When the isomer composition is not specified, all possible isomers are included.
  • the "pharmaceutically acceptable salt” mentioned in this specification includes, but is not limited to, salts formed with inorganic acids and salts formed with organic acids.
  • the salt formed with an inorganic acid may be selected from, for example, hydrochloride, phosphate, diphosphate, hydrobromide, sulfate, sulfinate, and nitrate.
  • the salt formed with organic acid can be selected from, for example, maleate, fumarate, tartrate, succinate, citrate, lactate, methanesulfonate, p-toluenesulfonate, 2-hydroxyethyl Sulfonate, benzoate, salicylate, stearate, alkanoate (such as acetate) and the salt formed with HOOC-(CH 2 ) n -COOH, where n is 0 to 4.
  • pharmaceutically acceptable cations include, but are not limited to, sodium, potassium, calcium, aluminum, lithium, and ammonium.
  • the free base can be obtained by alkalizing a solution of the acid salt.
  • the product is a free base
  • the free base can be prepared by dissolving the free base in a suitable organic solvent and treating the solution with an acid, and then preparing the addition salt (e.g., pharmaceutically Acceptable addition salt).
  • the addition salt e.g., pharmaceutically Acceptable addition salt.
  • Treatment refers to administering at least one compound and/or at least one stereoisomer and/or at least one pharmaceutically acceptable salt thereof to a subject in need, such as a cancer patient .
  • the “effective amount” in the present specification refers to at least one compound and/or at least one stereoisomer thereof and/or at least one pharmaceutically acceptable compound that effectively “treats” the subject’s disease or condition
  • the amount of salt has a certain degree of correlation with the biological or medical response of the tissue, system, animal or human being administered, for example, it is sufficient to prevent the development of one or more diseases or disorders to a certain extent or reduce One or more conditions or symptoms of the condition being treated.
  • the therapeutically effective amount will vary depending on the compound, the disease and its severity, and the age and weight of the mammal to be treated.
  • cancer in this specification refers to or describes a physiological condition in mammals that is typically characterized by cell growth disorders.
  • Tumor includes one or more cancer cells. Examples of cancer include, but are not limited to: carcinoma, lymphoma, blastoma, sarcoma, and leukemia or lymphoid malignancies.
  • cancers include squamous cell carcinoma (e.g., epithelial squamous cell carcinoma), lung cancer (including small cell lung cancer, non-small cell lung cancer (NSCLC), lung adenoma, and lung squamous cell carcinoma), peritoneal cancer, liver Cell cancer, gastric cancer (including gastrointestinal cancer), pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatocellular tumor, breast cancer, colon cancer, rectal cancer, colorectal cancer, intrauterine cancer Membranous or uterine cancer, salivary gland cancer, kidney cancer, prostate cancer, vulvar cancer, thyroid cancer, liver cancer, anal cancer, penile cancer, and head and neck cancer.
  • squamous cell carcinoma e.g., epithelial squamous cell carcinoma
  • lung cancer including small cell lung cancer, non-small cell lung cancer (NSCLC), lung adenoma, and lung squamous cell carcinoma
  • peritoneal cancer liver
  • the compound of the present invention, its stereoisomers and pharmaceutically acceptable salts thereof can be used alone or in combination with at least one other therapeutic agent for treatment.
  • the compound, its stereoisomers, and pharmaceutically acceptable salts thereof may be used in combination with at least one additional therapeutic agent.
  • the at least one additional therapeutic agent may be selected from anti-hyperproliferative agents, anti-cancer agents, and chemotherapeutic agents.
  • the compound and/or a pharmaceutically acceptable salt disclosed in this specification can be administered together with at least one other therapeutic agent in a single dosage form, or as a separate dosage form. When administered as a separate dosage form, at least one other therapeutic agent may be administered before, at the same time, or after administration of the compound and/or one pharmaceutically acceptable salt disclosed in this specification.
  • chemotherapeutic agent in this specification refers to a chemical compound used to treat cancer regardless of its mechanism of action.
  • Chemotherapeutic agents include compounds used in "targeted therapy” and conventional chemotherapy. Suitable chemotherapeutic agents can be selected from: apoptosis-inducing agents, polynucleotides (such as ribozymes), polypeptides (such as enzymes), drugs, biomimetics, alkaloids, alkylating agents, antitumor antibiotics, antimetabolites , Hormones, platinum compounds, monoclonal antibodies that bind to anticancer drugs, toxins and/or radionuclides, biological response modifiers (such as interferons such as IFN- ⁇ and interleukins such as IL-2), adoptive immunotherapy agents , Hematopoietic growth factors, agents that induce tumor cell differentiation (such as all-trans retinoic acid), gene therapy agents, antisense therapy agents and nucleotides, tumor vaccines, and angiogenesis inhibitors.
  • chemotherapeutic agents include but are not limited to Erlotinib (Erlotinib, Genentech/OSI Pharm); Bortezomib (Bortezomib, Millennium Pharm); Fulvestrant (Fulvestrant, AstraZeneca); Sunitinib (Sunitinib, Pfizer); Letrozole (Letrozole, Novartis); Imatinib mesylate (Imatinib mesylate, Novartis); PTK787/ZK 222584 (Novartis); Oxaliplatin (Oxaliplatin, Sanofi); 5-FU (5-fluorouracil); leucovorin (Leucovorin); rapamycin (Rapamycin, sirolimus, Wyeth); Lapatinib (Lapatinib, GSK572016, Glaxo Smith Kline); Lonafarnib (SCH 66336); Sorafenib (Sorafenib, Bayer); Irir
  • “Chemotherapeutic agents” can also be selected from: (i) anti-hormonal drugs used to modulate or inhibit the effect of hormones on tumors, such as anti-estrogens and selective estrogen receptor modulators. modulators, SERM), containing tamoxifen (including Tamoxifen citrate (tamoxifen citrate), raloxifene (raloxifene), droloxifene (droloxifene), 4-hydroxytamoxifen (4-hydroxytamoxifen), trioxifene (trioxifene), Raloxifene (keoxifene), LY117018, onapristone (onapristone) and (ii) Aromatase inhibitors that inhibit aromatase that regulates estrogen production in the adrenal glands, such as 4(5)-imidazole, aminoglutethimide, (Megestrol acetate), (Exemestane; Pfizer), Formestanie, Fadrozole, (Vorazole), (L
  • the "chemotherapeutic agent” can also be selected from therapeutic antibodies, such as alemtuzumab antibody (Campath), bevacizumab antibody ( Genentech); Cetuximab antibody ( Imclone); Pamucin monoclonal antibody ( Amgen), rituximab antibody ( Genentech/Biogen personal), Pertuzumab Monoclonal Antibody (OMNITARG TM , 2C4, Genentech), Trastiz Monoclonal Antibody ( Genentech), Tosimol monoclonal antibody (Bexxar, Corixia), and antibody drug conjugates, gemtuzumab monoclonal antibody ogamicin ( Wyeth).
  • therapeutic antibodies such as alemtuzumab antibody (Campath), bevacizumab antibody ( Genentech); Cetuximab antibody ( Imclone); Pamucin monoclonal antibody ( Amgen), rituximab antibody ( Genentech/Biogen personal), Pertuzumab Monoclonal Antibody (
  • a humanized monoclonal antibody with therapeutic potential as a chemotherapeutic agent, and its target compound, its stereoisomers and pharmaceutically acceptable salts thereof can be selected from: alemtuzumab, apolizumab Strain antibody (apolizumab), aselizumab, atlizumab, bapineuzumab, bevacizumab, bevacizumab Bivatuzumab mertansine, cantuzumab mertansine, cedelizumab, certolizumab pegol, cidfusituzumab, cidtuzumab, dacli Antibodies (daclizumab), eculizumab, efalizumab, epratuzumab, erlizumab, panvirizumab Antibody (felvizumab), Fontolizumab (fontolizumab), Gemtuzumab ozogamicin (gemtuzumab ozogamici
  • test examples are used to further illustrate the present invention, so as to benefit those who are generally knowledgeable in the technical field to which the present invention belongs, to fully utilize and practice the present invention without excessive interpretation. These test examples should not be regarded as It limits the scope of the present invention, but is used to illustrate how to implement the materials and methods of the present invention.
  • the present invention proposes a novel use of an ADAM9 inhibitor, which is applied to the preparation of immunomodulators.
  • the compound of formula (I) is used as an example of ADAM9 inhibitor to illustrate that ADAM9 inhibitor has the scope of the present invention. Please effect.
  • the derivatives with the structure represented by formula (I) of the embodiments of the present invention are designed and synthesized for the structure that can inhibit the activity of ADAM9, and the molecular docking method is used to actually screen the compound structure that can be suitable for the catalytic site of the metalloprotease domain of ADAM9 .
  • Example 1 a derivative of compound 6X-0310 was selected in Example 1 to Example 32 for testing.
  • the selected compounds were compound 4X-0296, compound SW1, compound 2X-0295, compound SW2, compound 12W-0264, and compound 6X-0310.
  • the test also includes compound 9R-0655, compound MS-1176, compound 5W-0369, and compound 161 that do not have compound 6X-0310 as the core structure.
  • FIG. 1A shows that Bm7 lung cancer cells were treated with the aforementioned compound 6X-0310 derivatives, and then cultured under non-attachment culture conditions, and then the expressions of ADAM9 and CDCP1 in Bm7 lung cancer cells were detected by Western blot method, where EF1 ⁇ is Internal reference, the negative control group is Bm7 lung cancer cells without treatment.
  • the results in Figure 1A show that compound 4X-0296, compound SW1, compound 2X-0295, compound SW2, compound 12W-0264, and compound 6X-0310 can all reduce the performance of CDCP1.
  • Example 1 to Example 32 were further subjected to cytotoxicity determination to measure the IC 50 value of the compound of formula (I) of the present invention in lung cancer cell lines.
  • Figure 1B shows the cytotoxicity assay results of compound 9R-0655, compound 4X-0296, compound SW1, compound 2X-0295, compound SW2, compound 12W-0264, compound MS-1176 and compound 6X-0310 on Bm7 lung cancer cells
  • Figure and Table 2 are the cytotoxicity assay results of different tumor cell lines in Example 1 to Example 32, where "+" indicates the effect of inhibiting tumor cell growth, and the number is the IC 50 value (unit: ⁇ M).
  • Example 1 to Example 32 are effective for kidney cancer cells (293), breast cancer cells (231-brm) and different lung cancer cells (A549, H1299, TC1, Bm7brmx2, Bm7brmx2-1st, Bm7brmx2). -2nd and PE10WBC) have toxic effects, and compared with the core structure-compound 6X-0310, compound SW1, compound SW2, compound 12W-0264, compound 2X-0295 and compound 4X-0296 have more tumor cytotoxic effects , Especially compound SW1 and compound SW2.
  • Fig. 2A, Fig. 2B, Fig. 2C, Fig. 2D, Fig. 2E, Fig. 2F, Fig. 2G, and Fig. 2H are graphs showing the characteristics analysis results of the compound SW1 and the compound SW2 in the in vitro test of the embodiment of the present invention.
  • Figure 2A shows the analysis of the inhibitory activity of ADAM9 with different concentrations of compound SW1 and SW2
  • Figure 2B shows the analysis of the inhibitory activity of ADAM17 with different concentrations of compound SW1 and SW2.
  • the results of Figures 2A and 2B show that compound SW1 and compound SW2 It has a similar inhibitory effect on ADAM9 activity and is dose-dependent, but compound SW1 and compound SW2 have no inhibitory effect on ADAM17.
  • control Bm7 lung cancer cells (shGFP treated) and ADAM9 were eliminated Bm7 lung cancer cells (treated shADAM9) were treated with 25 ⁇ M compound SW1 or compound SW2, respectively, and then cell migration was inhibited. Determination. Please refer to Figure 2C, the results show that the treatment of compound SW1 or compound SW2 can significantly reduce the migration ability of control Bm7 lung cancer cells.
  • compound SW1 and compound SW2 can block the anti-anoikis ability of cancer cells.
  • compound SW1 and compound SW2 can affect lung cancer brain metastasis cell line-Bm7brmx2, breast cancer brain metastasis cell line- under non-attachment culture conditions.
  • the results show that compound SW1 and compound SW2 can induce cell death under non-attachment culture conditions, and provide good therapeutic effects in the breast cancer brain metastasis cell line-MDA-231brm.
  • the statistical data is the mean ⁇ SD of 6 independent wells .
  • the results show that the treatment of compound SW1 or compound SW2 can greatly reduce the planting efficiency of control Bm7 lung cancer cells and wild-type TC1 lung cancer cells, showing that it can reduce the growth of control Bm7 lung cancer cells and wild-type TC1 lung cancer cells.
  • the Bm7 lung cancer cells were treated with 25 ⁇ M compound SW1 or compound SW2 for 12 hours, and the number of cancer cell spheres formed by them was determined.
  • the negative control group is Bm7 lung cancer cells without treatment.
  • the results show that the treatment of compound SW1 and compound SW2 can greatly reduce the number of cancer cell spheroids (* means p ⁇ 0.05, ** means p ⁇ 0.01).
  • ADAM9 excluding TC1 lung cancer cells
  • FIG. 3 is the analysis result diagram of the effect of removing ADAM9 on tumor growth, which is the photo diagram and statistical result diagram of the tumor tissue size of mice in the TC1-wild type group and the TC1-ADAM9 removal group.
  • the results in Figure 3 show that the removal of TC1 lung cancer cells by ADAM9 reduced the tumor size and metastatic nodules in the subcutaneous lung tumor mouse model.
  • ADAM9 gene deletion also affects the immune response of lung metastatic tumors
  • TC1-wild type group and TC1-ADAM9 knock-out group on the 28th day after the cell injection, take out their lung tissues, and immunize the lung tissue sections
  • Chemical staining method analyzes the immune cell map, and counts the number of immune cells in each range of the immunohistochemical staining method analysis result map.
  • Figure 5A and Figure 5B are the results of the analysis of the effect of removing ADAM9 on lung metastatic tumor growth and immune cell infiltration.
  • Figure 5B is for T cells (CD3), macrophages (F4/80) and neutrophils.
  • the antibody of MPO performs immunohistochemical staining of inflammatory cells in lung tissues to detect the expression of T cells, macrophages and neutrophils in tumor tissues of TC1-wild type group and TC1-ADAM9 knock-out group .
  • the results of Figures 5A and 5B show that the elimination of TC1 lung cancer cells by ADAM9 reduces the size of lung metastatic tumors.
  • increased CD8 + T cell infiltration can be detected in the tumors of mice in the TC1-ADAM9 elimination group, and The number of neutrophils is reduced.
  • ADAM9 gene has an impact on tumor growth and immune cell infiltration.
  • This experiment further conducted a comprehensive analysis of genes involved in ADAM9-mediated immunosuppression through lung tumor RNA sequencing, and found that ADAM9 in cancer cells may affect the microenvironment The immune cells interact with them, which in turn contributes to the occurrence, development and metastasis of tumors.
  • ADAM9-mediated tumor genes 329 Genes. Please refer to Table 6 for the functional analysis of 329 ADAM9-mediated tumor genes affected in cultured cells and tumors.
  • ADAM9-mediated tumor genes act to regulate IFN- ⁇ and the cytokines that produce and respond to IFN- ⁇ . Therefore, in the experiment, the target cells of C57BL/6 mice (wild type TC1 lung cancer cells or ADAM9 excluding TC1 lung cancer cells) and effector cells (spleen cells of C57BL/6 mice) were co-cultured at a ratio of 1:40 for 24 hours. The apoptosis rate was measured to verify the aforementioned analysis results.
  • FIG. 6 is the result of the analysis of the apoptosis rate of the target cells and effector cells after 24 hours of co-cultivation, where wild-type means wild-type TC1 lung cancer cells, and ADAM9 knockout means ADAM9 knocks out TC1 lung cancer cells.
  • wild-type means wild-type TC1 lung cancer cells
  • ADAM9 knockout means ADAM9 knocks out TC1 lung cancer cells.
  • ADAM9 inhibitors In order to further evaluate whether the treatment of ADAM9 inhibitors will give the same results as the ADAM9 gene knockout, wild-type TC1 lung cancer cells were injected subcutaneously into C57BL/6 mice with normal immunity to establish a subcutaneous lung tumor mouse model. And the ADAM9 inhibitor (compound SW1, 10 mg/kg) was treated by subcutaneous injection. From day 15 to day 24, compound SW1 was injected once a day for 9 days. And observe the tumor volume on the 12th, 20th and 27th day respectively.
  • Figure 7A is a graph showing the analysis results of the anti-tumor effects of ADAM9 inhibitors.
  • the control group was injected with DMSO as a control for the treatment of ADAM9 inhibitors.
  • FIG. 7B is a flow chart of ADAM9 inhibitors used in the treatment of syngeneic orthotopic breast tumor animal models.
  • 4T1-luc breast cancer cells (5 ⁇ 10 4 ) were transplanted into the breast fat pad of BALB/c mice to establish a syngeneic in situ breast tumor animal model.
  • the IVIS imaging system was used to detect the tumor size. The luminous flux is expressed.
  • ADAM9 inhibitor compound SW1, 10 mg/kg
  • the ADAM9 inhibitor compound SW1, 10 mg/kg
  • the surgically resected syngeneic orthotopic breast tumor animal model tumors were stained by immunohistochemistry.
  • another control group was injected with DMSO as a control for the treatment of ADAM9 inhibitors.
  • Figure 8A and Figure 8B are the results of the analysis of the effect of ADAM9 inhibitors on immune cell infiltration.
  • Figure 8A is the analysis result of calculated infiltrating T cells and neutrophils in a primary 4T1 breast tumor
  • Figure 8B is the analysis result of calculated infiltrating T cells and neutrophils in a lung metastatic breast tumor.
  • the results of Fig. 8A and Fig. 8B show that the number of infiltrating T cells increased after 4T1 breast tumors were treated with an ADAM9 inhibitor (compound SW1), especially lung metastatic breast tumors. In 4T1 primary breast tumors and lung metastatic breast tumors, the number of infiltrating neutrophils was significantly reduced. Shows that ADAM9 inhibitors can increase infiltrating T cells in 4T1 breast tumors and reduce infiltrating neutrophils.
  • ADAM9 inhibitors and checkpoint inhibitors have a synergistic effect.
  • TC1 subcutaneous lung tumor mice were treated with ADAM9 inhibitor (compound SW1), checkpoint inhibitor (anti-PDL1 antibody) and co-treatment ADAM9 inhibitor (compound SW1) and checkpoint inhibitor (anti-PDL1 antibody), and analyze the ratio of CD8 + T cells and regulatory T cells (T Reg ) in tumors of TC1 subcutaneous lung tumor mice.
  • the experiment also included a control group of treated vehicle (DMSO).
  • FIG. 10A, FIG. 10B and FIG. 10C are graphs showing the analysis results of ADAM9 inhibitors to stimulate tumor cells to secrete cytokines.
  • the results of Figure 10A to Figure 10C show that treatment of compound SW1 can increase the performance of CXCL10, CXCL11, CXC3CL1 and IFNB in human colon cancer cells, human pancreatic cancer cells and human esophageal cancer cells, showing that ADAM9 inhibitors can stimulate cancer cell secretion and immunity Activate related cytokines.
  • the present invention proposes a new use of an ADAM9 inhibitor, which can be used as an immunomodulator to enhance the effectiveness of cancer immunotherapy. And through experimental data, it can reduce tumor growth, change the tumor microenvironment, stimulate immune cells to infiltrate the tumor, stimulate cancer cells to secrete cytokines related to immune activation, and then can be used to treat tumors resistant to immunotherapy . Therefore, ADAM9 inhibitors can be used in cancer immunotherapy and can treat cancer, and they can have a synergistic effect when formulated with inspection inhibitors, and can also increase the effectiveness of cancer immunotherapy, and have the potential to be used in the biomedical health care market.

Landscapes

  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Immunology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Endocrinology (AREA)
  • Mycology (AREA)
  • Microbiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

ADAM9抑制剂用于制备免疫调节剂的用途，免疫调节剂可以改变肿瘤内免疫细胞的分布和增加免疫细胞的浸润，增强癌症免疫疗法的有效性。

Description

ADAM9抑制剂作为免疫调节剂的用途 技术领域
本发明是有关于一种ADAM9抑制剂的用途，特别是ADAM9抑制剂作为免疫调节剂的用途。
背景技术
癌症又名为恶性肿瘤，为细胞不正常增生，且这些增生的细胞可能侵犯身体的其他部分，为由控制细胞分裂增殖机制失常而引起的疾病。全世界罹患癌症的人口有不断增加的趋势，癌症是国人十大死因之一，且已连续二十七年为居十大死因的榜首。癌转移的发生为癌症高死亡的主因，如肺癌发生脑转移的预后极差。即使早期的肺癌病人可以开刀切除肿瘤，仍有25％将发展成远程癌转移。常见的抗癌药物虽可用于抑制癌细胞生长，但对防止癌复发仍有限。针对促进转移的分子作用可视为前瞻的作法。
含有去整合素和金属蛋白酶结构域的蛋白质9(Disintegrin and metalloproteinase domain-containing protein 9,ADAM9)在许多肿瘤中过度表达，例如胰腺癌、乳腺癌、前列腺癌和肺癌，且ADAM9高表现量与癌症病人预后差有关，可当作预测标记。因ADAM9表达可帮助肿瘤细胞适应不利的环境，使ADAM9被认为可促进肿瘤发展，并且被认为是比其他与癌症相关的金属蛋白酶更好的治疗靶点。ADAM9因具有切割和释放许多参与癌症进展相关分子的能力而参与肿瘤发生(tumorigenesis)，由于其能够切割和释放参与癌症进展的许多分子而参与肿瘤发生，并且肿瘤周围的基质细胞所分泌的ADAM9可通过新血管形成(neovascularization)促进肿瘤发展。
先前研究的结果显示，抑制ADAM9表达及其下游信号传导可显著延长肺肿瘤小鼠的存活时间。而从肺癌和乳腺癌的临床样本明显可见，肿瘤标本中ADAM9表现水平低的患者存活时间长于ADAM9表现水平高的患者。此外，由于ADAM9缺陷鼠并无明显表型，代表以ADAM9当标靶蛋白可能有良好的药物耐受性。
发明内容
本发明的一态样是在提供一种ADAM9抑制剂的用途，其应用于制备免疫调节剂。
依据前述的ADAM9抑制剂的用途，其中所述免疫调节剂可用于增强癌症免疫疗法的有效性。较佳地，所述癌症免疫疗法的施用对象可为免疫功能低下的患者。
依据前述的ADAM9抑制剂的用途，其中所述免疫调节剂可用于刺激免疫细胞浸润到肿瘤中。较佳地，所述免疫细胞可为T细胞、自然杀手细胞、巨噬细胞、嗜中性球、树突状细胞或骨髓来源的抑制细胞。
依据前述的ADAM9抑制剂的用途，其中所述免疫调节剂可用于改变肿瘤微环境的趋化因子种类。
依据前述的ADAM9抑制剂的用途，其中所述免疫调节剂可用于处理具有免疫治疗抗性的肿瘤。较佳地，所述具有免疫治疗抗性的肿瘤可对检查点抑制剂、过继细胞转移、治疗性抗体、治疗疫苗、细胞因子、免疫细胞疗法或其组合具有抗性。其中所述检查点抑制剂可为抗CTLA-4抗体、抗PDL1抗体或抗PD-1抗体。
依据前述的ADAM9抑制剂的用途，其中所述免疫调节剂可与一检查点抑制剂共同配制。较佳地，所述检查点抑制剂可为抗CTLA-4抗体、抗PDL1抗体或抗PD-1抗体。
依据前述的ADAM9抑制剂的用途，其中所述ADAM9抑制剂可为式(I)的化合物，或其医药上可接受的盐类或立体异构体，
Figure PCTCN2020086642-appb-000001
其中R为包含0至3个独立地选自氮、硫和氧的杂原子的C 1-C 18的烃基，或为经选自氮、硫和氧的杂原子取代的包含0至3个独立地选自氮、硫和氧的 杂原子的C 1-C 18的烃基，且R包含C 5-C 10有机环，该有机环为包含0至3个独立地选自氮、硫和氧的杂原子的芳基。
依据前述的ADAM9抑制剂的用途，其中R可为NHR 1，且R 1为2-噻唑-4-基-乙基-异吲哚啉-1,3-二酮。
借此，本发明实施例的ADAM9抑制剂能通过改变肿瘤内免疫细胞的分布，增加免疫细胞的浸润，而具有免疫调节功能，适用于制备免疫调节剂。
附图说明
为让本发明的上述和其他目的、特征、优点与实施例能更明显易懂，所附图式的说明如下：
图1A和图1B为式(I)化合物抑制ADAM9活性的分析结果图；
图2A、图2B、图2C、图2D、图2E、图2F、图2G和图2H为式(I)化合物于体外试验的特性分析结果图；
图3为剔除ADAM9对于肿瘤生长影响的分析结果图；
图4A、图4B、图4C和图4D为剔除ADAM9后肿瘤组织中ADAM9、CD4、CD8和IFN-γ的RNA分析结果图；
图5A和图5B为剔除ADAM9对于肺转移性肿瘤生长和免疫细胞浸润影响的分析结果图；
图6为共同培养目标细胞和效应细胞24小时后的细胞凋亡率分析结果图；
图7A为ADAM9抑制剂抗肿瘤作用的分析结果图；
图7B为ADAM9抑制剂用于治疗同基因原位乳腺肿瘤动物模型的流程图；
图8A和图8B为ADAM9抑制剂对于免疫细胞浸润影响的分析结果图；
图9为共同处理ADAM9抑制剂和检查点抑制剂的分析结果图；以及
图10A、图10B和图10C为ADAM9抑制剂刺激肿瘤细胞分泌细胞因子的分析结果图。
具体实施方式
以下对于特定实施方式和实施例的描述仅用于说明而非为限制，对本发明所属领域的技术人员而言可依据其所进行各种修改或改变各种非关键参数以 产生基本相似结果。本发明提供多种实施方式。
本发明提供一种ADAM9抑制剂的用途，其应用于制备免疫调节剂。所述免疫调节剂可用于刺激免疫细胞浸润到肿瘤中。较佳地，所述免疫细胞可为T细胞、自然杀手细胞、巨噬细胞、嗜中性球、树突状细胞或骨髓来源的抑制细胞。此外，所述免疫调节剂可用于改变肿瘤微环境的趋化因子种类或用于增强癌症免疫疗法的有效性。特别是，所述癌症免疫疗法的施用对象可为免疫功能低下的患者。
本发明另提供一种ADAM9抑制剂的用途，其应用于制备免疫调节剂。所述免疫调节剂可用于处理具有免疫治疗抗性的肿瘤。较佳地，所述具有免疫治疗抗性的肿瘤可对检查点抑制剂、过继细胞转移、治疗性抗体、治疗疫苗、细胞因子、免疫细胞疗法或其组合具有抗性。其中所述检查点抑制剂可为在免疫细胞活化中用于抑制免疫检查点蛋白的分子，较佳地，可为抗CTLA-4抗体、抗PDL1抗体或抗PD-1抗体。
前述的ADAM9抑制剂还可以与检查点抑制剂搭配使用，以增强癌症免疫疗法的有效性。此外，前述的ADAM9抑制剂还可以与化学治疗剂和/或检查点抑制剂搭配使用，以作为治疗癌症的医药组合物。
所述ADAM9抑制剂可为式(I)的化合物，或其医药上可接受的盐类或立体异构体，
Figure PCTCN2020086642-appb-000002
其中R为包含0至3个独立地选自氮、硫和氧的杂原子的C 1-C 18的烃基，或为经选自氮、硫和氧的杂原子取代的包含0至3个独立地选自氮、硫和氧的杂原子的C 1-C 18的烃基，且R包含C 5-C 10有机环，该有机环为包含0至3个独立地选自氮、硫和氧的杂原子的芳基。
依据前述的式(I)化合物，其中R可为二级胺、酰胺、NHR 1、NHCOR 2或如式(i)所示的一结构：
Figure PCTCN2020086642-appb-000003
其中R 1可为包含0至3个独立地选自氮、硫和氧的杂原子的芳基。较佳地，R 1可为2-噻唑-4-基-乙基-异吲哚啉-1,3-二酮(2-thiazol-4-yl-ethyl-isoindoline-1,3-dione)。R 2可为包含0至3个独立地选自氮、硫和氧的杂原子的苯基或苯并杂环基。较佳地，R 2可为苯并噻吩(benzothiophene)。R 3可为任选地取代包含0至3个独立地选自氮、硫和氧的杂原子的苯基、苯并杂环基或杂环基。
除非另有说明，本文中及本说明书所述的「一」及「一个」意指文章中的文法对象为一或多个(即至少一个)。此外，类别为包含于该类别的所有成员的缩写，例如，C 1-C 3的烷基为对所有C 1-C 3的烷基的缩写，举例而言，C 1-C 3的烷基包含甲基、乙基、丙基及其异构体。
下列用语、词组和符号通常旨在具有以下阐述的含义，除非使用它们的上下文中另有说明。以下缩写词和术语具有指示的含义。
本说明书所述的「烯基」是指选自包含至少一个C＝C双键和碳原子数为2-18个、2-12个或2-6个的直链和支链的烃基。烯基的实例可选自但不限于乙烯基或乙烯基、丙-1-烯基、丙-2-烯基、2-甲基丙-1-烯基、丁-1-烯基、丁-2-烯基、丁-3-烯基、丁-1,3-二烯基、2-甲基丁-1,3-二烯、己-1-烯基、己-2-烯基、己-3-烯基、己-4-烯基和六-1,3-二烯基团。
本说明书所述的「芳基」是指选自以下的基团：5-和6-元碳环芳环，例如苯基、双环系统和三环系统。其中所述的双环系统可为7-12元双环系统，其中至少一个环是碳环和芳香环，其选自但不限于萘、二氢化茚和1,2,3,4-四氢喹啉。所述的三环系统可为10-15元三环系统，其中至少一个环是碳环和芳香 环，例如芴。举例而言，芳基选自与任选地包含至少一个选自氮、氧和硫的杂原子的5-至7-元环烷基或杂环稠合的5-和6-元碳环芳环。当碳环芳环与杂环稠合时，连接点在碳环芳环上，当碳环芳环与环烷基稠合时，连接点可以在碳环芳环或环烷基上。由取代的苯衍生物形成并在环原子上具有自由价的二价基团被称为取代的亚苯基基团。通过从具有自由价的碳原子移除一个氢原子而源于名称以“-基(-idene)”结尾的单价多环烃基团的二价基团通过添加“-亚基(-yl)”至相应单价基团的名称中来命名，例如具有两个连接点的萘基被称为亚萘基。然而，芳基不包含杂芳基或与杂芳基重迭，本说明书下文分别定义。因此，如果一个或多个碳环芳环与杂环芳环稠合，则所得的环系统是杂芳基，而非本说明书所定义的芳基。
本说明书所述的「杂芳基」是指选自以下的基团：5-至7-元芳族单环，包含1、2、3或4个选自氮、氧和硫的杂原子，其余的环原子为碳；包含1、2、3或4个选自氮、氧和硫的杂原子的8-至12-元双环，其余环原子为碳，并且其中至少一个环为芳族且至少一个杂原子存在于芳香环。例如，杂芳基包含与5-至7-元环烷基环稠合的5-至7-元杂环芳环。前述稠合的双环杂芳基环系统，其中仅一个环包含至少一个杂原子，连接点可以在杂芳环或环烷基环上。当杂芳基中硫和氧原子的总数超过1时，该些杂原子彼此不相邻。在一些实施方案中，杂芳基中硫和氧原子的总数不大于2，在另一些实施方案中，芳族杂环中硫和氧原子的总数不大于1。杂芳基的实例包含但不限于(从分配优先级1的链接位置开始编号)吡啶基(如2-吡啶基、3-吡啶基或4-吡啶基)、喹啉基、吡嗪基、2,4-嘧啶基、3,5-嘧啶基、2,4-咪唑基、咪唑并吡啶基、异恶唑基、恶唑基、噻唑基、异噻唑基、噻二唑基、四唑基、噻吩基、三嗪基、苯并噻吩基、呋喃基、苯并呋喃基、苯并咪唑基、吲哚基、异吲哚基、二氢吲哚基、酞嗪基、吡嗪基、哒嗪基、吡咯基、三唑基、喹啉基、异喹啉基、吡唑基、吡咯并吡啶基(如1H-吡咯并[2,3-b]吡啶-5-基)、吡唑并吡啶基(如1H-吡唑并[3,4-b]吡啶-5-基)、苯并恶唑基(如苯并[d]恶唑-6-基)、哌啶基、嘌呤基、1-氧杂-2,3-二唑基、1-氧杂-2,4-二唑基、1-氧杂-2,5-二唑基、1-氧杂-3,4-二唑基、1-噻吩-3,4-二唑基、呋喃基、苯并呋咱基、苯并噻吩基、苯并噻唑基、苯并恶唑基、喹唑啉基、喹喔啉基、萘啶基、呋喃并吡啶基、苯并噻唑基(如苯并[d]噻唑-6-基)、吲唑基(如1H-吲唑)-5-基)和5,6,7,8-四氢异喹啉。
化合物可含有不对称中心，因此可作为镜像异构物存在。当化合物具有两个或更多个不对称中心时，可另外作为非镜像异构物存在。镜像异构物和非镜像异构物属于更广泛的立体异构体类别。所有可能的立体异构体包含如实质上纯的可分离的镜像异构物、其外消旋混合物以及非镜像异构物的混合物。化合物的所有立体异构体和/或其药学上可接受的盐皆被包含在适用的情况下。除非另有说明，否则提及的异构体适用于任何可能的异构体。而当异构体组合物未指定时，包含所有可能的异构体。
本说明书所述的「药学上可接受的盐」包含但不限于与无机酸形成的盐以及与有机酸形成的盐。与无机酸形成的盐可选自例如盐酸盐、磷酸盐、二磷酸盐、氢溴酸盐、硫酸盐、亚磺酸盐和硝酸盐。与有机酸形成的盐可选自例如马来酸盐、富马酸盐、酒石酸盐、琥珀酸盐、柠檬酸盐、乳酸盐、甲磺酸盐、对甲苯磺酸盐、2-羟乙基磺酸盐、苯甲酸盐、水杨酸盐、硬脂酸盐、链烷酸盐(例如乙酸盐)以及与HOOC-(CH 2) n-COOH形成的盐，其中n为0至4。药学上可接受的阳离子的实例包含但不限于钠、钾、钙、铝、锂和铵。
此外，若化合物是作为酸加成盐，则可以通过碱化酸式盐的溶液来获得游离碱。相反，如果产物是游离碱，则可以通过将游离碱溶解在合适的有机溶剂中并以酸处理所述溶液，再依照碱化合物制备酸加成盐的常规方法来制备加成盐(例如药学上可接受的加成盐)。本领域技术人员可在没有过度实验的情况下使用的各种合成方法来制备无毒的药学上可接受的加成盐。
本说明书所述的「治疗」是指将至少一种化合物和/或至少一种立体异构体和/或至少一种其药学上可接受的盐施用予有需要的受试者，例如癌症患者。
本说明书所述的「有效量」是指有效「治疗」受试者的疾病或病症的至少一种化合物和/或其至少一种立体异构体和/或至少一种其药学上可接受的盐的量。有效量与所施用的组织、系统、动物或人的生物或医学反应有一定程度上的相关性，例如当施用时其足以在一定程度上防止一种或多种疾病或病症的发展或减轻一种或多种所治疗的病症或病症的症状。治疗有效量将根据化合物、疾病及其严重程度以及待治疗的哺乳动物的年龄和体重等而变化。
本说明书所述的「癌症」是指或描述哺乳动物中以细胞生长失调为典型特征的生理状况。「肿瘤」包括一种或多种癌细胞。癌症的实例包含但不限于:癌、淋巴瘤、母细胞瘤、肉瘤和白血病或淋巴恶性肿瘤。此类癌症的更具体的 实例包含鳞状细胞癌(例如上皮鳞状细胞癌)、肺癌(包含小细胞肺癌、非小细胞肺癌(NSCLC)、肺腺瘤和肺鳞癌)、腹膜癌、肝细胞癌、胃癌(包含胃肠癌)、胰腺癌、成胶质细胞瘤、宫颈癌、卵巢癌、肝癌、膀胱癌、肝细胞瘤、乳腺癌、结肠癌、直肠癌、结直肠癌、子宫内膜癌或子宫癌、唾液腺癌、肾癌、前列腺癌、外阴癌、甲状腺癌、肝癌、肛门癌、阴茎癌，以及头颈癌。
本发明的化合物、其立体异构体及其药学上可接受的盐可单独使用或与至少一种其它治疗剂合并使用进行治疗。在一些实施方案中，化合物、其立体异构体及其药学上可接受的盐可以与至少一种另外的治疗剂合并使用。所述至少一种另外的治疗剂可以选自抗过度增殖剂、抗癌剂和化学治疗剂。本说明书揭示的化合物和/或一种药学上可接受的盐可以与单一剂型中的至少一种其他治疗剂一起施用，或作为单独剂型施用。当作为单独剂型施用时，可以在施用本说明书揭示的化合物和/或一种药学上可接受的盐之前，同时或之后施用至少一种其他治疗剂。
本说明书所述的「化学治疗剂」是指用于治疗癌症的化学化合物而不论其作用机理。化学治疗剂包含用于「靶向治疗」和常规化疗的化合物。合适的化学治疗剂可以选自：诱导细胞凋亡试剂、多核苷酸(例如核酶)、多肽(例如酶)、药物、生物模拟物、生物碱、烷化剂、抗肿瘤抗生素、抗代谢药物、激素、铂化合物、与抗癌药物、毒素和/或放射性核素结合的单株抗体、生物反应调节剂(例如IFN-α等干扰素和IL-2等白细胞介素)、过继免疫治疗剂、造血生长因子、诱导肿瘤细胞分化的药剂(例如全反式维甲酸)、基因治疗试剂、反义治疗试剂和核苷酸、肿瘤疫苗以及血管生成抑制剂。
化学治疗剂的实例包含但不限于厄洛替尼(Erlotinib,
Figure PCTCN2020086642-appb-000004
Genentech/OSI Pharm)；硼替佐米(Bortezomib,
Figure PCTCN2020086642-appb-000005
Millennium Pharm)；氟维司群(Fulvestrant,
Figure PCTCN2020086642-appb-000006
AstraZeneca)；舒尼替尼(Sunitinib,
Figure PCTCN2020086642-appb-000007
辉瑞)；来曲唑(Letrozole,
Figure PCTCN2020086642-appb-000008
诺华)；甲磺酸伊马替尼(Imatinib mesylate,
Figure PCTCN2020086642-appb-000009
Novartis)；PTK787/ZK 222584(诺华)；奥沙利铂(Oxaliplatin,
Figure PCTCN2020086642-appb-000010
Sanofi)；5-FU(5-氟尿嘧啶)；亚叶酸钙(Leucovorin)；雷帕霉素(Rapamycin,西罗莫司,
Figure PCTCN2020086642-appb-000011
Wyeth)；拉帕替尼(Lapatinib,
Figure PCTCN2020086642-appb-000012
GSK572016,Glaxo Smith Kline)；洛那法尼(Lonafarnib,SCH 66336)；索拉非尼(Sorafenib,
Figure PCTCN2020086642-appb-000013
拜耳)；伊立替康 (Irinotecan,
Figure PCTCN2020086642-appb-000014
辉瑞)和吉非替尼(Gefitinib,
Figure PCTCN2020086642-appb-000015
阿斯特捷利康)；AG1478、AG1571(SU 5271,Sugen)；烷基化剂，例如噻替哌(thiotepa)和环磷酰胺(cyclophosphamide)；烷基磺酸盐，例如白消安(busulfan)、英丙舒凡(improsulfan)和呱泊舒凡(piposulfan)；氮杂环庚烷，例如苯并二氮(benzodepa)、碳喹啉(carboquone)、美妥替哌(meturedopa)和乌瑞替哌(uredopa)；乙烯亚胺和甲基蜜胺类，例如六甲蜜胺(altretamine)、三亚乙基蜜胺(triethylenemelamine)、三亚乙基磷酰胺(triethylenephosphoramide)、三亚乙基硫代磷酰胺(triethylenethiophosphoramide)和三羟甲基蜜胺(trimethylolomelamine)；乙酰生合成物(acetogenins)，例如布拉它辛(bullatacin)和布拉它辛酮(bullatacinone)；喜树碱(camptothecin)，例如合成类似物托泊替康(topotecan)；苔藓抑素(bryostatin)；海绵多烯酮(callystatin)、CC-1065及其阿多来新(adozelesin)、卡折来新(carzelesin)和比折来新(bizelesin)合成类似物；隐藻素(cryptophycins)，例如隐藻素I和隐藻素8；多拉司他汀(dolastatin)；倍癌霉素(duocarmycin)及其合成类似物(例如KW-2189和CB1-TM1)；艾槽素(eleutherobin)；水鬼蕉碱(pancratistatin)；sarcodictyin；海绵抑素(spongistatin)；氮芥类(nitrogen mustards)，例如苯丁酸氮芥(chlorambucil)、萘氮芥(chlornaphazine)、胆磷酰胺(cholophosphamide)、雌莫司汀(estramustine)、异环磷酰胺(ifosfamide)、双氯乙基甲胺(mechlorethamine)、盐酸氧氮芥(mechlorethamine oxide hydrochloride)、美法仑(melphalan)、新氮芥(novembichin)、苯芥胆甾醇(phenesterine)、泼尼莫司汀(prednimustine)、曲磷胺(trofosfamide)、尿嘧啶芥末(uracil mustard)；亚硝基脲类，例如卡莫司汀(carmustine)、氯脲菌素(chlorozotocin)、福莫司汀(fotemustine)、洛莫司汀(lomustine)、尼莫司汀(nimustine)和雷莫司汀(ranimustine)；抗生素类，例如烯二炔类抗生素(enediyne)(例如加利车霉素(calicheamicin)，尤其是加利车霉素γ1I和加利车霉素ωI1；蒽环类抗生素(dynemicin)，包括dynemicin A；二膦酸盐类(bisphosphonates)，例如氯膦酸盐(clodronate)；埃斯波霉素(esperamicin)；以及新制癌素(neocarzinostatin)发色团和相关色蛋白烯二炔类抗生素发色团、阿克拉霉素(aclacinomycin)、放线菌素(actinomycin)、氨茴霉素(anthramycin)、偶氮丝氨酸(azaserine)、博来霉素(bleomycin)、放线菌素C(cactinomycin)、carabicin、洋红霉素(carminomycin)、嗜癌霉素(carzinophilin)、色霉素(chromomycin)、放线菌素D(dactinomycin)、 柔红霉素(daunorubicin)、地托比星(detorubicin)、6-二氮-5-氧-L-正亮氨酸；
Figure PCTCN2020086642-appb-000016
多柔比星(doxorubicin)，包含吗啉代多柔比星、氰基吗啉代多柔比星、2-吡咯代多柔比星和脱氧多柔比星；表柔比星(epirubicin)、依索比星(esorubicin)、伊达比星(idarubicin)、麻西罗霉素(marcellomycin)、丝裂霉素类(mitomycins)例如丝裂霉素C、霉酚酸(mycophenolic acid)、诺拉霉素(nogalamycin)、橄榄霉素(olivomycin)、培洛霉素(peplomycin)、泊非霉素(potfiromycin)、嘌呤霉素(puromycin)、三铁阿霉素(quelamycin)、罗多比星(rodorubicin)、链黑菌素(streptonigrin)、链佐星(streptozocin)、杀结核菌素(tubercidin)、乌苯美司(ubenimex)、净司他丁(zinostatin)、佐柔比星(zorubicin)；抗代谢物类，例如甲氨蝶呤(methotrexate)和5-氟尿嘧啶(5-FU)；叶酸类似物，例如二甲叶酸(denopterin)、甲氨蝶呤(methotrexate)、蝶罗呤(pteropterin)、三甲曲沙(trimetrexate)；嘌呤类似物，例如氟达拉滨(fludarabine)、6-巯基嘌呤(mercaptopurine)、硫咪嘌呤(thiamiprine)、硫鸟嘌呤(thioguanine)；嘧啶类似物，例如安西他滨(ancitabine)、阿扎胞苷(azacitidine)、6-氮尿苷(azauridine)、卡莫氟(carmofur)、阿糖胞苷(cytarabine)、双脱氧尿苷(dideoxyuridine)、脱氧氟尿苷(doxifluridine)、依诺他滨(enocitabine)、氟尿苷(floxuridine)；雄激素类，例如卡鲁睾酮(calusterone)、丙酸屈他雄酮(dromostanolone propionate)、表硫雄醇(epitiostanol)、美雄烷(mepitiostane)、睾内酯(testolactone)；抗肾上腺类，例如氨鲁米特(aminoglutethimide)、米托坦(mitotane)、曲洛司坦(trilostane)；叶酸补充剂，例如亚叶酸(folinic acid)；醋葡醛内酯(aceglatone)；醛磷酰胺糖苷(aldophosphamide glycoside)；氨基乙酰丙酸(aminolevulinic acid)；恩尿嘧啶(eniluracil)；安吖啶(amsacrine)；bestrabucil；比生群(bisantrene)；依达曲沙(edatraxate)；地磷酰胺(defosfamide)；地美可辛(demecolcine)；地吖醌(diaziquone)；elfornithine；依利醋铵(elliptinium acetate)；埃坡霉素(epothilone)；依托格鲁(etoglucid)；硝酸镓；羟脲(hydroxyurea)；香菇多糖(lentinan)；氯尼达明(lonidamine)；美登木素生物碱类(maytansinoids)，例如美登素(maytansine)和安丝菌素(ansamitocin)；米托胍腙(mitoguazone)；米托蒽醌(mitoxantrone)；莫呱达醇(mopidamol)；二胺硝吖啶(nitracrine)；喷司他丁(pentostatin)；蛋氨氮芥(phenamet)；吡柔比星(pirarubicin)；洛索蒽醌(losoxantrone)；鬼臼酸(podophyllinic acid)；2-乙基酰肼(ethylhydrazide)；丙卡巴肼(procarbazine)；多 糖复合物(JHS Natural Products，Eugene，OR)；雷佐生(razoxane)；根霉素(rhizoxin)；西佐喃(sizofiran)；螺旋锗(spirogermanium)；细交链孢菌酮酸(tenuazonic acid)；三亚胺醌(triaziquone)；2，2'，2″-三氯三乙胺；单端孢菌素类(trichothecenes)，尤其是T-2毒素、疣孢菌素(verrucarin)A、杆孢菌素(roridin)A和蛇行菌素(anguidin)；乌拉坦(urethan)；长春地辛(vindesine)；达卡巴嗪(dacarbazine)；甘露莫司汀(mannomustine)；二溴甘露醇(mitobronitol)；二溴卫矛醇(mitolactol)；呱泊溴烷(pipobroman)；gacytosine；阿糖胞苷(arabinoside)(“Ara-C”)；环磷酰胺(cyclophosphamide)；塞替派(thiotepa)；类紫杉醇类(taxoids)，例如
Figure PCTCN2020086642-appb-000017
帕利他塞(paclitaxel,Bristol-Myers Squibb Oncology，Princeton，N.J.)、
Figure PCTCN2020086642-appb-000018
不含克列莫佛(Cremophor)、清蛋白改造纳米颗粒剂型帕利他塞(American Pharmaceutical Partners,Schaumberg,Illinois)和
Figure PCTCN2020086642-appb-000019
多西他塞(doxetaxel,Rhone-Poulenc Rorer,Antony,France)；苯丁酸氮芥(chlorambucil)；
Figure PCTCN2020086642-appb-000020
吉西他滨(gemcitabine)；6-硫鸟嘌呤(thioguanine)；巯基嘌呤(mercaptopurine)；甲氨蝶呤(methotrexate)；铂类似物，例如顺铂(cisplatin)、奥沙利铂(oxaliplatin)和卡铂(carboplatin)；长春碱(vinblastine)；铂(platinum)；依托泊苷(etoposide)(VP-16)；异环磷酰胺(ifosfamide)；米托蒽醌(mitoxantrone)；长春新碱(vincristine)；
Figure PCTCN2020086642-appb-000021
长春瑞滨(vinorelbine)；能灭瘤(novantrone)；替尼泊苷(teniposide)；依达曲沙(edatrexate)；道诺霉素(daunomycin)；氨基蝶呤(aminopterin)；希罗达(xeloda)；伊本膦酸盐(ibandronate)；伊立替康(irinotecan)(Camptosar，CPT-11)；拓扑异构酶抑制剂RFS 2000；二氟甲基鸟氨酸(DMFO)；类维生素A(例如维甲酸)；以及上述任一种药学上可接受的盐、酸和衍生物。
「化学治疗剂」还可以选自：(i)用来调节或抑制激素对肿瘤的作用的抗激素药，例如抗雌激素(anti-estrogens)和选择性雌激素受体调节剂(selective estrogen receptor modulators,SERM)，包含他莫昔芬(tamoxifen)(包括
Figure PCTCN2020086642-appb-000022
他莫昔芬柠檬酸盐(tamoxifen citrate))、雷洛昔芬(raloxifene)、屈洛昔芬(droloxifene)、4-羟基他莫昔芬(4-hydroxytamoxifen)、曲沃昔芬(trioxifene)、雷洛昔芬(keoxifene)、LY117018、奥那司酮(onapristone)和
Figure PCTCN2020086642-appb-000023
(ii)抑制调节肾上腺中的雌激素生成的芳香酶的芳香酶抑制剂，例如4(5)-咪唑、氨鲁米特(aminoglutethimide)、
Figure PCTCN2020086642-appb-000024
(醋酸甲地孕酮)、
Figure PCTCN2020086642-appb-000025
(依西美坦；辉瑞)、福美坦(formestanie)、法罗唑(fadrozole)、
Figure PCTCN2020086642-appb-000026
(伏罗唑)、
Figure PCTCN2020086642-appb-000027
(来曲唑；诺华)和
Figure PCTCN2020086642-appb-000028
(阿那罗唑；阿斯特捷利康)；(iii)抗雄激素类，例如氟他胺(flutamide)、尼鲁米特(nilutamide)、比卡鲁胺(bicalutamide)、亮丙瑞林(leuprolide)和戈舍瑞林(goserelin)；以及曲沙他滨(troxacitabine)(1,3-二氧戊环胞嘧啶核苷类似物)；(iv)蛋白激酶抑制剂，例如MEK抑制剂(W02007/044515)；(v)脂质激酶抑制剂；(vi)反义寡核苷酸，特别是抑制与异常的细胞增殖相关的信号转导途径中的基因例如PKC-α、Raf和H-Ras；(vii)核酶，例如VEGF表达抑制剂(例如
Figure PCTCN2020086642-appb-000029
)和HER2表达抑制剂；(viii)疫苗，例如基因治疗疫苗，例如
Figure PCTCN2020086642-appb-000030
和
Figure PCTCN2020086642-appb-000031
rlL-2；拓扑异构酶I抑制剂，例如
Figure PCTCN2020086642-appb-000032
和
Figure PCTCN2020086642-appb-000033
rmRH；(ix)抗血管生成剂，例如贝伐珠单抗(
Figure PCTCN2020086642-appb-000034
Genentech)；以及上述任一种的药学可接受的盐、酸和衍生物。
「化学治疗剂」也可以选自治疗性抗体，例如阿仑珠单株抗体(Campath)、贝伐珠单株抗体(
Figure PCTCN2020086642-appb-000035
Genentech)；西妥昔单株抗体(
Figure PCTCN2020086642-appb-000036
Imclone)；帕木单株抗体(
Figure PCTCN2020086642-appb-000037
Amgen)、利妥昔单株抗体(
Figure PCTCN2020086642-appb-000038
Genentech/Biogen Idee)、帕妥珠单株抗体(OMNITARG TM,2C4,Genentech)、曲司珠单株抗体(
Figure PCTCN2020086642-appb-000039
Genentech)、托西莫单株抗体(Bexxar,Corixia)，以及抗体药物偶联物，吉妥珠单株抗体奥加米星(
Figure PCTCN2020086642-appb-000040
Wyeth)。
具有作为化学治疗剂的治疗潜力的人源化单株抗体，与其目标化合物、其立体异构体及其药学上可接受的盐可以选自：阿仑珠单抗(alemtuzumab)、阿泊珠单株抗体(apolizumab)、阿塞珠单株抗体(aselizumab)、阿利珠单株抗体(atlizumab)、巴匹珠单株抗体(bapineuzumab)、贝伐单株抗体(bevacizumab)、比伐珠单株抗体美登素(bivatuzumab mertansine)、美坎珠单株抗体美登素(cantuzumab mertansine)、西利珠单株抗体(cedelizumab)、赛妥珠单株抗体(certolizumab pegol)、cidfusituzumab、cidtuzumab、达珠单株抗体(daclizumab)、依库珠单株抗体(eculizumab)、依法利珠单株抗体(efalizumab)、依帕珠单株抗体(epratuzumab)、厄利珠单株抗体(erlizumab)、泛维珠单株抗体(felvizumab)、芳妥珠单株抗体(fontolizumab)、吉妥珠单株抗体奥佐米星(gemtuzumab ozogamicin)、伊珠单株抗体奥佐米星(inotuzumab ozogamicin)、伊匹木单株抗体(ipilimumab)、拉贝珠单株抗体(labetuzumab)、林妥珠单抗(lintuzumab)、马 妥珠单株抗体(matuzumab)、美泊利单株抗体(mepolizumab)、莫维珠单株抗体(motavizumab)、motovizumab、那他珠单株抗体(natalizumab)、尼妥珠单抗(nimotuzumab)、nolovizumab、numavizumab、奥瑞珠单株抗体(ocrelizumab)、奥马珠单株抗体(omalizumab)、帕利珠单株抗体(palivizumab)、帕考珠单株抗体(pascolizumab)、pecfusituzumab、pectuzumab、帕妥珠单株抗体(pertuzumab)、培克珠单株抗体(pexelizumab)、ralivizumab、雷珠单株抗体(ranibizumab)、瑞利珠单株抗体(reslivizumab)、瑞利珠单株抗体(reslizumab)、resyvizumab、罗维珠单株抗体(rovelizumab)、卢利珠单株抗体(ruplizumab)、西罗珠单株抗体(sibrotuzumab)、西利珠单株抗体(siplizumab)、松妥珠单株抗体(sontuzumab)、他珠单株抗体替塞坦(tacatuzumab tetraxetan)、他度珠单株抗体(tadocizumab)、他利珠单株抗体(talizumab)、替非珠单株抗体(tefibazumab)、托珠单株抗体(tocilizumab)、托利珠单株抗体(toralizumab)、曲妥珠单株抗体(trastuzumab)、西莫白介素单株抗体(tucotuzumab celmoleukin)、tucusituzumab、umavizumab、乌珠单株抗体(urtoxazumab)和维西珠单株抗体(visilizumab)。
兹以下列具体试验例进一步示范说明本发明，用以有利于本发明所属技术领域通常知识者，可在不需过度解读的情形下完整利用并实践本发明，而不应将这些试验例视为对本发明范围的限制，但用于说明如何实施本发明的材料及方法。
本发明提出一种ADAM9抑制剂的新颖用途，其应用于制备免疫调节剂，于本发明的说明书中以式(I)化合物作为ADAM9抑制剂的实施例，以说明ADAM9抑制剂具有本发明范围所请的功效。
一、式(I)化合物的化学合成与结构鉴定
本发明实施例的具有式(I)所示结构的衍生物，针对能抑制ADAM9活性的结构设计合成，并使用分子对接方法来实际筛选可以适合ADAM9的金属蛋白酶结构域的催化位点的化合物结构。
请参照下表一，为式(I)化合物的实施例1至实施例32的结构式。
表一
Figure PCTCN2020086642-appb-000041
Figure PCTCN2020086642-appb-000042
Figure PCTCN2020086642-appb-000043
Figure PCTCN2020086642-appb-000044
Figure PCTCN2020086642-appb-000045
Figure PCTCN2020086642-appb-000046
Figure PCTCN2020086642-appb-000047
Figure PCTCN2020086642-appb-000048
Figure PCTCN2020086642-appb-000049
试验上于实施例1至实施例32中选择化合物6X-0310的衍生物进行试验。所挑选出的化合物分别为化合物4X-0296、化合物SW1、化合物2X-0295、化合物SW2、化合物12W-0264和化合物6X-0310。试验上另包含非以化合物6X-0310为核心结构的化合物9R-0655、化合物MS-1176、化合物5W-0369和化合物161。
请参照图1A、图1B和表二，为式(I)化合物抑制ADAM9活性的分析结果图。图1A为将Bm7肺癌细胞分别处理前述的化合物6X-0310的衍生物后，在无贴附培养条件下进行培养，再以西方墨点法侦测Bm7肺癌细胞中ADAM9和CDCP1表现，其中EF1α为内部参照，阴性对照组为未处理药物的Bm7肺癌细胞。图1A的结果显示，化合物4X-0296、化合物SW1、化合物2X-0295、化合物SW2、化合物12W-0264和化合物6X-0310皆可降低CDCP1的表现。试验上进一步将实施例1至实施例32的式(I)化合物进行细胞毒性测定，以测量本发明的式(I)化合物在肺癌细胞系中的IC 50值，测试结果请参照图1B和表二，图1B为化合物9R-0655、化合物4X-0296、化合物SW1、化合物2X-0295、化合物SW2、化合物12W-0264、化合物MS-1176和化合物6X-0310对Bm7肺癌细胞的细胞毒性测定分析结果图，表二为实施例1至实施例32的对不同的肿瘤细胞株的细胞毒性测定分析结果，其中「+」表示具有抑制肿瘤细胞生长的效果，数字为IC 50值(单位为μM)。
表二
Figure PCTCN2020086642-appb-000050
Figure PCTCN2020086642-appb-000051
Figure PCTCN2020086642-appb-000052
图1B和表二的结果显示，实施例1至实施例32对于肾脏癌细胞(293)、乳癌细胞(231-brm)和不同的肺癌细胞(A549、H1299、TC1、Bm7brmx2、Bm7brmx2-1st、Bm7brmx2-2nd和PE10WBC)均有毒杀作用，且与核心结构-化合物6X-0310相比，化合物SW1、化合物SW2、化合物12W-0264、化合物 2X-0295和化合物4X-0296具有更加地肿瘤细胞毒杀效果，特别是化合物SW1和化合物SW2。
试验上进一步利用Autodock v.4.2计算基质金属蛋白酶(Matrix metalloproteinase,MMP)抑制剂-CGS27023A(Novartis)和化合物SW1和化合物SW2的Ki(抑制常数)，以评估其是否为潜在的ADAM9抑制剂。评估结果请参照表三。
表三
化合物 结合能(kcal) Ki(抑制常数)
CGS27023A -6.64 13470nM
SW1 -9.49 100nM
SW2 -9.49 100nM
表三的结果显示，化合物SW1和化合物SW2的Ki值均低于MMP抑制剂-CGS27023A，预测其可以较低浓度达到与较高浓度的CGS27023A相同的抑制ADAM9活性效果。
二、式(I)化合物的抑制ADAM9活性的效果
为了测量式(I)化合物抑制ADAM9活性的功效，试验上使用重组人类ADAM9和荧光肽底物(R&D系统)建立了ELISA系统，其中包含广效型MMP抑制剂-BB-94作为正对照组，而于此试验中所使用的式(I)化合物为化合物SW1和化合物SW2。
图2A、图2B、图2C、图2D、图2E、图2F、图2G和图2H，为本发明实施例的化合物SW1和化合物SW2于体外试验的特性分析结果图。
图2A为以不同浓度的化合物SW1和化合物SW2进行抑制ADAM9活性分析，图2B为以不同浓度的化合物SW1和化合物SW2进行抑制ADAM17活性分析，图2A和图2B的结果显示，化合物SW1和化合物SW2对于ADAM9活性具有相似抑制效果，且为剂量依赖性，但化合物SW1和化合物SW2对于ADAM17皆不具有抑制效果。
为了进一步评估化合物SW1和化合物SW2的特异性，试验上将对照Bm7肺癌细胞(处理过shGFP)和ADAM9剔除Bm7肺癌细胞(处理过shADAM9)分别处理25μM的化合物SW1或化合物SW2，再进行细胞迁移抑制测定。请参照图2C，结果显示，处理化合物SW1或化合物SW2可以显著降低了对照Bm7 肺癌细胞的迁移能力。
为了验证化合物SW1和化合物SW2可阻断癌细胞的抗失巢凋亡能力，试验上测定化合物SW1和化合物SW2在无贴附培养条件下对肺癌脑转移细胞系-Bm7brmx2、乳癌脑转移细胞系-MDA-231brm和白血球中失巢凋亡(无贴附诱导的细胞凋亡)的IC 50值(单位为μM)。请参照下表四，结果显示化合物SW1和化合物SW2可以在无贴附培养条件下诱导细胞死亡，并且在乳癌脑转移细胞系-MDA-231brm中提供良好的治疗效果。
表四
Figure PCTCN2020086642-appb-000053
进一步测试处理过化合物SW1和化合物SW2的肿瘤细胞的种植效率，试验上先将对照Bm7肺癌细胞(处理过shGFP)和ADAM9剔除Bm7肺癌细胞(处理过shADAM9)分别处理20μM的化合物SW1或化合物SW2，以及将野生型TC1肺癌细胞和ADAM9剔除TC1肺癌细胞分别处理10μM的化合物SW1或化合物SW2，再以菌落形成测定(colony-forming assay)确认各试验组的种植效率。请参照图2D和图2E，其中阴性对照组为未经化合物SW1或化合物SW2处理的肿瘤细胞株，菌落形成测定的代表性图像显示在底部，统计数据为6个独立的孔的平均值±SD。结果显示，处理化合物SW1或化合物SW2可以大幅降低对照Bm7肺癌细胞和野生型TC1肺癌细胞的种植效率，显示其可降低对照Bm7肺癌细胞和野生型TC1肺癌细胞的生长。
试验上进一步将野生型TC1肺癌细胞和ADAM9剔除TC1肺癌细胞以化合物SW1或化合物SW2处理24小时后，再以Annexin V和PI染色，侦测细胞的凋亡状况。请参照图2F，其中Annexin V +细胞(凋亡细胞)百分比为3次独立实验的统计结果，具有平均值±SD。图2F的结果显示，与ADAM9剔除TC1肺癌细胞相比，化合物SW1和化合物SW2可以显著降低对照肺癌细胞生长并诱导细胞凋亡。
此外，试验上另检测化合物SW1和化合物SW2对于胰腺癌细胞的IC 50值(单位为μM)，结果请参照图2G和下表五。结果显示，本发明的化合物SW1 和化合物SW2对于不同的胰腺癌细胞皆具有毒杀作用。
表五
胰腺癌细胞 SW2 SW1
Panc-1 34.2 424
MiaPaCa 8.5 -
PC-080 89.6 446
Pan18-GFP-Luc 112 0.3
Su86-86-GFP-Luc 66.8 59.2
HPAC-GFP-Luc 29.3 126.5
试验上另将Bm7肺癌细胞分别处理25μM的化合物SW1或化合物SW2后12小时，测定其形成癌细胞球体的数量。请参照图2H，其中阴性对照组为未处理药物的Bm7肺癌细胞。结果显示，处理化合物SW1和化合物SW2可以大幅降低癌细胞球体的形成数量(*表示p<0.05，**表示p<0.01)。
三、ADAM9抑制剂用于癌症免疫治疗的效果
为了验证ADAM9对于肿瘤进展免疫反应的影响，试验上分别将野生型TC1肺癌细胞(n＝10)和ADAM9剔除TC1肺癌细胞(n＝10)以皮下注射至具正常免疫力的C57BL/6小鼠中，以建立皮下肺肿瘤小鼠模型，并在细胞注射后第22天牺牲TC1-野生型组和TC1-ADAM9剔除组的小鼠，并取出其肿瘤组织，测量肿瘤组织的体积，以及每组三个单独的肿瘤样本利用RT-qPCR分析肿瘤组织中ADAM9、CD4、CD8和IFN-γ的RNA表现量。
请参照图3为剔除ADAM9对于肿瘤生长影响的分析结果图，其为TC1-野生型组和TC1-ADAM9剔除组的小鼠的肿瘤组织大小照片图和统计结果图。图3的结果显示，ADAM9剔除TC1肺癌细胞减少了皮下肺肿瘤小鼠模型中的肿瘤大小和转移性结节。
请再参照图4A、图4B、图4C和图4D，为剔除ADAM9后肿瘤组织中ADAM9、CD4、CD8和IFN-γ的RNA分析结果图，其中野生型表示TC1-野生型组的小鼠，剔除表示TC1-ADAM9剔除组的小鼠。结果显示，在TC1-ADAM9剔除组的小鼠的肿瘤中CD8和IFN-γ的RNA过度表达。由于在培养的ADAM9剔除TC1肺癌细胞中均未检测到CD8和IFN-γ，但在 TC1-ADAM9剔除组的小鼠的肿瘤中却检测到CD8和IFN-γ的过度表达，前述结果显示ADAM9基因剔除增加了肿瘤组织中CD8 +T细胞的浸润和IFN-γ的表达，可诱导抑制TC1肿瘤进展的免疫反应。
为了进一步确认ADAM9基因剔除是否也会影响肺转移肿瘤的免疫反应，试验上将野生型TC1肺癌细胞(n＝5)和ADAM9剔除TC1肺癌细胞(n＝5)以尾静脉注射至具正常免疫力的C57BL/6小鼠中，以建立肺转移模型，并在细胞注射后第28天牺牲TC1-野生型组和TC1-ADAM9剔除组的小鼠，取出其肺脏组织，对肺脏组织切片进行免疫组织化学染色法分析免疫细胞图谱，并统计免疫组织化学染色法分析结果图每个范围内的免疫细胞数。
请参照图5A和图5B，为剔除ADAM9对于肺转移性肿瘤生长和免疫细胞浸润影响的分析结果图，其中图5B为针对T细胞(CD3)、巨噬细胞(F4/80)和嗜中性球(MPO)的抗体对肺脏组织中的炎症细胞进行免疫组织化学染色，以侦测TC1-野生型组和TC1-ADAM9剔除组的肿瘤组织中T细胞、巨噬细胞和嗜中性球的表现。图5A和图5B的结果显示，ADAM9剔除TC1肺癌细胞减少了肺转移性肿瘤的大小，此外，可在TC1-ADAM9剔除组的小鼠的肿瘤中侦测到增加的CD8 +T细胞浸润，而嗜中性球细胞的数量减少。
由前述结果可见ADAM9基因对于肿瘤生长和免疫细胞浸润具有影响，本试验进一步地通过肺肿瘤RNA定序参与ADAM9介导的免疫抑制的基因进行全面分析，发现癌细胞中的ADAM9可能影响微环境中的免疫细胞并与之相互作用，进而有助于肿瘤的发生、发展和转移。为了更精确鉴定ADAM9调控的基因，我们鉴定了表达图谱在癌细胞系与TC1-野生型组和TC1-ADAM9剔除组的小鼠的皮下肿瘤中一致的基因，作为ADAM9介导的肿瘤基因(329个基因)。请参照表六，为在培养的细胞和肿瘤中影响的329个ADAM9介导的肿瘤基因的功能分析。
表六
功能 基因编号 -log(p值)
调节细胞因子的生产 18 6.1
多细胞生物过程的正调控 20 5.3
多细胞生物过程的负调控 15 5.2
对β干扰素的反应 5 4.8
对γ干扰素的反应 6 4.6
白血球的连系或滚动 4 4.6
免疫系统的负调控 11 4.5
对病毒的防御反应 9 4.4
由前述分析可见，ADAM9介导的肿瘤基因作用于调节IFN-γ以及生产和响应IFN-γ的细胞因子。因此试验上将C57BL/6小鼠的目标细胞(野生型TC1肺癌细胞或ADAM9剔除TC1肺癌细胞)和效应细胞(C57BL/6小鼠的脾细胞)以1:40的比例共培养24小时后，测定细胞凋亡率，以验证前述分析结果。
请参照图6，为共同培养目标细胞和效应细胞24小时后的细胞凋亡率分析结果图，其中野生型表示野生型TC1肺癌细胞，ADAM9剔除表示ADAM9剔除TC1肺癌细胞。结果显示，野生型TC1肺癌细胞比ADAM9剔除TC1肺癌细胞对免疫细胞攻击的抵抗力更高。这些结果表明肿瘤中ADAM9的剔除可以增加免疫细胞的浸润，并且会对免疫细胞的反应更加敏感。
为了进一步评估处理ADAM9抑制剂是否会得到与ADAM9基因剔除的相同结果，试验上将野生型TC1肺癌细胞以皮下注射至具正常免疫力的C57BL/6小鼠中，建立皮下肺肿瘤小鼠模型，并通过皮下注射处理ADAM9抑制剂(化合物SW1，10mg/kg)。从第15天到第24天，每天注射1次化合物SW1，持续9天。并分别在第12天、第20天和第27天观察肿瘤体积。
请参照图7A，为ADAM9抑制剂抗肿瘤作用的分析结果图。其中对照组为注射DMSO作为处理ADAM9抑制剂的对照。图7A的结果显示，与处理DMSO的对照组相比，处理化合物SW1减少了皮下肺肿瘤小鼠的肿瘤生长(每组N＝5)。
请再参照图7B，为ADAM9抑制剂用于治疗同基因原位乳腺肿瘤动物模型的流程图。试验上另将4T1-luc乳癌细胞(5×10 4)移植至BALB/c小鼠的乳腺脂肪垫中建立了同基因原位乳腺肿瘤动物模型，利用IVIS成像系统进行检测，肿瘤大小以IVIS图像的光通量表示。在第15天检测到肿瘤图像之后，通过皮下注射于第16天、第18天和第20天预处理ADAM9抑制剂(化合物SW1，10mg/kg)。并于第21进行手术切除肿瘤后，再于第23天、第25天、第27天、第29天和第31天继续处理ADAM9抑制剂(化合物SW1，10mg/kg)。其中手术切除的同基因原位乳腺肿瘤动物模型肿瘤进行免疫组织化学染色。试验上另 有对照组注射DMSO作为处理ADAM9抑制剂的对照。
请再参照图8A和图8B，为ADAM9抑制剂对于免疫细胞浸润影响的分析结果图。其中图8A为于原发性4T1乳腺肿瘤计算浸润的T细胞和嗜中性球的分析结果，图8B为肺转移性乳腺肿瘤计算浸润的T细胞和嗜中性球的分析结果。图8A和图8B的结果显示，4T1乳腺肿瘤经由ADAM9抑制剂(化合物SW1)治疗后，浸润性T细胞数量增加，特别是肺转移性乳腺肿瘤。而在4T1原发性乳腺肿瘤和肺部转移性乳腺肿瘤中，浸润性嗜中性球数量皆大幅减少。显示ADAM9抑制剂可增加4T1乳腺肿瘤中浸润的T细胞，并减少浸润性嗜中性球。
进一步地我们欲分析ADAM9抑制剂和检查点抑制剂是否具有协同作用，试验上将TC1皮下肺肿瘤小鼠单独处理ADAM9抑制剂(化合物SW1)、检查点抑制剂(抗-PDL1抗体)和共同处理ADAM9抑制剂(化合物SW1)和检查点抑制剂(抗-PDL1抗体)，并分析TC1皮下肺肿瘤小鼠的肿瘤中CD8 +T细胞和调节性T细胞(T Reg)的比率。试验上另包含处理载体(DMSO)的对照组。
请参照图9，为共同处理ADAM9抑制剂和检查点抑制剂的分析结果图。结果显示，与处理载体、单独处理化合物SW1和抗-PDL1抗体的组别相比，在共同处理化合物SW1和抗-PDL1抗体的组别中，CD8 +T细胞和调节性T细胞(T Reg)的比率显著地增加，显示ADAM9抑制剂和检查点抑制剂具有协同作用。
我们进一步地分析处理ADAM9抑制剂是否会刺激肿瘤细胞分泌细胞因子，以激活ADAM9抑制剂抗肿瘤免疫力。试验上分别以12.5μM的化合物SW1处理人类结肠癌细胞SW620和人类胰腺癌细胞PANC-1，以及以5μM的化合物SW1处理人类食道癌细胞CE146T，24小时后收集细胞并利用RT-qPCR侦测CXCL10、CXCL11、CXC3CL1和IFNB的RNA表现量。其中CXCL10、CXCL11和CXCL1为促进CD8 +T细胞免疫应答的细胞因子，IFNB为具有抗癌作用的细胞因子。
请参照图10A、图10B和图10C，为ADAM9抑制剂刺激肿瘤细胞分泌细胞因子的分析结果图。图10A至图10C的结果显示，处理化合物SW1可以增加人类结肠癌细胞、人类胰腺癌细胞和人类食道癌细胞中CXCL10、CXCL11、CXC3CL1和IFNB的表现，显示ADAM9抑制剂可以刺激癌细胞分 泌与免疫激活相关的细胞因子。
综上所述，本发明提出了一种ADAM9抑制剂的新用途，其可做为免疫调节剂，用于增强癌症免疫疗法的有效性。并经由实验数据证实，其可降低肿瘤的生长、改变肿瘤的微环境、刺激免疫细胞浸润到肿瘤中、刺激癌细胞分泌与免疫激活相关的细胞因子，进而可用于处理具有免疫治疗抗性的肿瘤。是以ADAM9抑制剂可用于癌症免疫治疗并可治疗癌症，且其可与检查抑制剂共同配制时具有协同作用，还能增加癌症免疫疗法的有效性，具有运用于生医保健市场的潜能。
然本发明已以实施方式揭露如上，然其并非用以限定本发明，任何熟习此技艺者，在不脱离本发明的精神和范围内，当可作各种的更动与润饰，因此本发明的保护范围当视后附的申请专利范围所界定者为准。

Claims (13)

  1. 一种ADAM9抑制剂的用途，其特征在于，用于制备一免疫调节剂。
  2. 根据权利要求1所述的ADAM9抑制剂的用途，其特征在于，该免疫调节剂用于增强一癌症免疫疗法的有效性。
  3. 根据权利要求2所述的ADAM9抑制剂的用途，其特征在于，该癌症免疫疗法的施用对象为一免疫功能低下的患者。
  4. 根据权利要求2所述的ADAM9抑制剂的用途，其特征在于，该免疫调节剂用于刺激一免疫细胞浸润到一肿瘤中。
  5. 根据权利要求4所述的ADAM9抑制剂的用途，其特征在于，该免疫细胞为T细胞、自然杀手细胞、巨噬细胞、嗜中性球、树突状细胞或骨髓来源的抑制细胞。
  6. 根据权利要求2所述的ADAM9抑制剂的用途，其特征在于，该免疫调节剂用于改变肿瘤微环境的趋化因子种类。
  7. 根据权利要求2所述的ADAM9抑制剂的用途，其特征在于，该免疫调节剂用于处理一具有免疫治疗抗性的肿瘤。
  8. 根据权利要求7所述的ADAM9抑制剂的用途，其特征在于，该具有免疫治疗抗性的肿瘤对一检查点抑制剂、一过继细胞转移、一治疗性抗体、一治疗疫苗、一细胞因子、一免疫细胞疗法或其组合具有抗性。
  9. 根据权利要求8所述的ADAM9抑制剂的用途，其特征在于，该检查点抑制剂为一抗CTLA-4抗体、一抗PDL1抗体或一抗PD-1抗体。
  10. 根据权利要求1所述的ADAM9抑制剂的用途，其特征在于，该免疫调节剂与一检查点抑制剂共同配制。
  11. 根据权利要求10述的ADAM9抑制剂的用途，其特征在于，该检查点抑制剂为一抗CTLA-4抗体、一抗PDL1抗体或一抗PD-1抗体。
  12. 根据权利要求1至11任一所述的ADAM9抑制剂的用途，其特征在于，该ADAM9抑制剂为式(I)的化合物，或其医药上可接受的盐类或立体异构体，
    Figure PCTCN2020086642-appb-100001
    其中R为包含0至3个独立地选自氮、硫和氧的杂原子的C 1-C 18的烃基，或为经选自氮、硫和氧的杂原子取代的包含0至3个独立地选自氮、硫和氧的杂原子的C 1-C 18的烃基，且R包含C 5-C 10有机环，该有机环为包含0至3个独立地选自氮、硫和氧的杂原子的芳基。
  13. 根据权利要求12所述的ADAM9抑制剂的用途，其特征在于，R为NHR 1，且R 1为2-噻唑-4-基-乙基-异吲哚啉-1,3-二酮。
PCT/CN2020/086642 2019-04-26 2020-04-24 Adam9抑制剂作为免疫调节剂的用途 Ceased WO2020216319A1 (zh)

Priority Applications (3)

Application Number Priority Date Filing Date Title
US17/605,857 US20220202783A1 (en) 2019-04-26 2020-04-24 Use Of ADAM9 Inhibitor As Immunomodulator
CN202080031194.5A CN114173778B (zh) 2019-04-26 2020-04-24 Adam9抑制剂在制备用于制备免疫调节剂的药物中的应用
EP20796014.7A EP3960171B1 (en) 2019-04-26 2020-04-24 Use of adam9 inhibitor as immunomodulator

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201962839183P 2019-04-26 2019-04-26
US62/839,183 2019-04-26

Publications (1)

Publication Number Publication Date
WO2020216319A1 true WO2020216319A1 (zh) 2020-10-29

Family

ID=72940932

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2020/086642 Ceased WO2020216319A1 (zh) 2019-04-26 2020-04-24 Adam9抑制剂作为免疫调节剂的用途

Country Status (5)

Country Link
US (1) US20220202783A1 (zh)
EP (1) EP3960171B1 (zh)
CN (1) CN114173778B (zh)
TW (1) TWI735210B (zh)
WO (1) WO2020216319A1 (zh)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TW202438113A (zh) * 2023-03-24 2024-10-01 大陸商映恩生物製藥（蘇州）有限公司 標靶ａｄａｍ９的人源化抗體、其抗體藥物偶聯物及其應用

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004024089A2 (en) * 2002-09-11 2004-03-25 Sloan-Kettering Institute For Cancer Research Inhibition or activation of adam9 and adam15 for treatment of vascularization-related disease and wound healing
WO2007044515A1 (en) 2005-10-07 2007-04-19 Exelixis, Inc. Azetidines as mek inhibitors for the treatment of proliferative diseases
CN109563152A (zh) * 2016-03-11 2019-04-02 普罗克斯马根有限责任公司 Cxcr4拮抗剂和免疫检查点抑制剂的组合
TW201917127A (zh) * 2017-10-29 2019-05-01 中國醫藥大學 用於抑制ａｄａｍ９活性之化合物、其醫藥組合物及其用途

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20070022197A (ko) * 2003-11-05 2007-02-26 팔링겐, 인코포레이티드 Ｃｄｉｍ 결합 항체의 증강된 ｂ 세포 세포독성
KR20230110820A (ko) * 2016-04-22 2023-07-25 오비아이 파머 인코퍼레이티드 글로보 계열 항원을 통한 면역 활성화 또는 면역 조정에의한 암 면역요법
CA3048211A1 (en) * 2016-12-23 2018-06-28 Macrogenics, Inc. Adam9-binding molecules, and methods of use thereof

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004024089A2 (en) * 2002-09-11 2004-03-25 Sloan-Kettering Institute For Cancer Research Inhibition or activation of adam9 and adam15 for treatment of vascularization-related disease and wound healing
WO2007044515A1 (en) 2005-10-07 2007-04-19 Exelixis, Inc. Azetidines as mek inhibitors for the treatment of proliferative diseases
CN109563152A (zh) * 2016-03-11 2019-04-02 普罗克斯马根有限责任公司 Cxcr4拮抗剂和免疫检查点抑制剂的组合
TW201917127A (zh) * 2017-10-29 2019-05-01 中國醫藥大學 用於抑制ａｄａｍ９活性之化合物、其醫藥組合物及其用途

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
PO-LIN KUO ET AL.: "Lung Cancer-derived Galectin-1 Enhances Tumorigenic Potentiation of Tumor-Associated Dendritic Cells by Expressing Heparin-Binding EGF-Like Growth Factor", THE JOURNAL OF BIOLOGICAL CHEMISTRY, vol. 287, no. 13, 30 January 2012 (2012-01-30), XP055746976, ISSN: 0021-9258, DOI: 10.1074/jbc.M111.321190 *
See also references of EP3960171A4
SOOYEON OH ET AL.: "A Disintegrin and Metalloproteinase 9 (ADAM9) in Advanced Hepatocellular Carcinoma and Their Role as a Biomarker during Hepatocellular Carcinoma Immunotherapy", CANCERS, vol. 12, no. 3, 21 March 2020 (2020-03-21), XP055746979, ISSN: 2070-6694, DOI: 10.3390/cancers12030745 *

Also Published As

Publication number Publication date
EP3960171A4 (en) 2023-05-24
EP3960171B1 (en) 2025-01-01
TWI735210B (zh) 2021-08-01
CN114173778A (zh) 2022-03-11
TW202038948A (zh) 2020-11-01
US20220202783A1 (en) 2022-06-30
CN114173778B (zh) 2024-12-27
EP3960171A1 (en) 2022-03-02

Similar Documents

Publication Publication Date Title
US10562899B2 (en) Fused tricyclic urea compounds as Raf kinase and/or Raf kinase dimer inhibitors
US11865114B2 (en) Method for treating diseases using SMARCA2/4 degraders
EP2797919B1 (en) Fused tetra or penta-cyclic pyridophthalazinones as parp inhibitors
US8609687B2 (en) Triazolopyridine JAK inhibitor compounds and methods
US9895376B2 (en) Fused tricyclic compounds as Raf kinase inhibitors
EP2265609B1 (en) Imdizo [4. 5-b] pyridine derivatives used as raf inhibitors
US20120157451A1 (en) Raf inhibitor compounds and methods of use thereof
US20110110889A1 (en) Raf inhibitor compounds and methods of use thereof
US20130018033A1 (en) Raf inhibitor compounds and methods of use thereof
US20120157452A1 (en) 1h-pyrazolo[3,4-b] pyridine compounds for inhibiting raf kinase
TWI735210B (zh) Ａｄａｍ９抑制劑作為免疫調節劑之用途
TWI695000B (zh) 用於抑制ａｄａｍ９活性之化合物、其醫藥組合物及其用途
HK1217485B (zh) 作为raf激酶和/或raf激酶二聚体抑制剂的稠合三环脲类化合物

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 20796014

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 2020796014

Country of ref document: EP

Effective date: 20211126

WWG Wipo information: grant in national office

Ref document number: 202080031194.5

Country of ref document: CN