Combined use of YAP / TAZ-TEAD interaction inhibitor and taxane drug

Abstract

The present disclosure relates to the field of biomedicine, and particularly relates to combined use of a YAP / TAZ-TEAD interaction inhibitor and a taxane compound. Specifically, the present disclosure provides use of the YAP / TAZ-TEAD interaction inhibitor in combination with a taxane drug in the preparation of a medicament for treating and / or preventing cancer. The combination of the YAP / TAZ-TEAD interaction inhibitor with the taxane drug exhibits more significant efficacy in treating cancer than the treatment with paclitaxel alone.

Description

Use of YAP / TAZ and TEAD interaction inhibitor in combination with taxane TECHNICAL FIELD

[0001] The present disclosure belongs to the field of biological medicine, and particularly relates to use of YAP / TAZ and TEAD interaction inhibitor in combination with taxane. BACKGROUND

[0002] YAP, as a transcription factor, does not contain a DNA binding region itself. After entering the nucleus, activated YAP must bind to a transcription factor to jointly exercise transcription function. The closest transcription factor that YAP binds to after entering the nucleus is TEAD. Human TEAD family proteins include TEAD1 / TEAD2 / TEAD3 / TEAD4. YAP, together with TEAD (or other transcription factors such as Smad1, RUNX, ErbB4 and p73), can initiate transcription of a series of downstream genes, including CTGF (connective tissue growth factor), Gli2, Birc5, Birc2, FGF1 (fibroblast growth factor 1) and AREG (amphiregulin). Most of the genes activated by the YAP transcription factor complex are related to cell growth and proliferation.

[0003] The Hippo-YAP pathway regulates the size and normal physiological function of organs by regulating cell proliferation and apoptosis, and is strictly regulated under normal physiological conditions. Inactivation of the protein kinase of the Hippo pathway or activation of YAP promotes tumorigenesis. In fact, abnormal activation of the Hippo pathway is a major event in the occurrence and development of various malignant tumors, and increased expression level and nuclear localization of YAP are found in tumors including non-small cell lung cancer, breast cancer, head and neck cancer, esophageal cancer, ovarian cancer, liver cancer, prostate cancer, mesothelioma and skin cancer.

[0004] Paclitaxel is a complex secondary metabolite in Taxus plants, an effective ingredient extracted or semi-synthesized from the trunk, bark or needle of Taxus trees, and is currently the only drug known to promote microtubule polymerization and stabilize polymerized microtubules. Through II-III clinical studies, paclitaxel is mainly suitable for ovarian cancer and breast cancer, and also has certain efficacy for lung cancer, colorectal cancer, melanoma, head and neck cancer, lymphoma, brain tumor. Due to its unique mechanism of action, it is effective for many drug-resistant patients and has become one of the most popular anti-tumor drugs. SUMMARY

[0005] The purpose of the present disclosure is to provide use of YAP / TAZ and TEAD interaction inhibitor in combination with taxane.

[0006] In a first aspect, the present disclosure provides a use of a YAP / TAZ-TEAD interaction inhibitor and a taxane drug in the preparation of a medicament for treating and / or preventing cancer.

[0007] In a second aspect, the present disclosure provides a pharmaceutical composition comprising a YAP / TAZ-TEAD interaction inhibitor, a taxane drug and a pharmaceutically acceptable carrier. BRIEF DESCRIPTION OF DRAWINGS

[0008] Figure 1 is a line graph showing the efficacy of a YAP / TAZ-TEAD interaction inhibitor (Compound 1) in combination with paclitaxel in a MDA-MB-231 xenograft model. DETAILED DESCRIPTION

[0009] The following detailed embodiments are provided so as to enable those skilled in the art to more clearly understand the present disclosure. It is noted that these embodiments are set forth merely for illustrative purposes and are not intended to limit the scope of the present application.

[0010] To enable those skilled in the art to have a better understanding of the features and effects of the present disclosure, the following is a general description and definition of the terms and phrases mentioned in the specification and claims. Unless otherwise specified, all technical and scientific words used herein have their usual meanings to those skilled in the art of the present disclosure, and in case of conflict, the definitions in the present specification shall prevail.

[0011] Theories or mechanisms described and disclosed herein, whether correct or not, should not be considered limiting on the scope of the present disclosure, i.e., the technical solutions of the present disclosure can be implemented without being limited by any particular theory or mechanism.

[0012] In the present disclosure, “comprising”, “including”, “containing” and similar phrases encompass the meanings of “consisting essentially of” and “consisting of”, e.g., when the present disclosure discloses “A comprising B and C”, “A consisting essentially of B and C” and “A consisting of B and C” should be considered to have been disclosed herein.

[0013] In the present disclosure, all features defined in the form of numerical ranges or percentage ranges, such as values, quantities, contents and concentrations, are for the sake of brevity and convenience. Therefore, the description of numerical ranges or percentage ranges should be considered to have encompassed and specifically disclosed all possible sub-ranges and individual values within the range (including integers and fractions).

[0014] In the present disclosure, unless otherwise specified, percentages refer to mass percentages and ratios refer to mass ratios.

[0015] In the description, specific terminology is used to describe particular features and / or embodiments so as to be thorough; however, the application can be practiced without resorting to the specific details. In other instances, well-known methods, procedures and components have not been described in detail so as not to obscure the description of the application. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. The terminology used in the description is for the purpose of describing particular embodiments only and is not intended to be limiting of the application.

[0016] In the description, specific terminology is used to describe particular features and / or embodiments so as to be thorough; however, the application can be practiced without resorting to the specific details. In other instances, well-known methods, procedures and components have not been described in detail so as not to obscure the description of the application. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. The terminology used in the description is for the purpose of describing particular embodiments only and is not intended to be limiting of the application.

[0017] I. Terminology

[0018] In the following description, certain specific details are set forth in order to provide a thorough understanding of the various embodiments. However, one skilled in the art will understand that the application can be practiced without some or all of these details. In other instances, well-known structures have not been described in detail in order to avoid obscuring the description of the described embodiments. Unless otherwise noted, the use of the

[0019] Reference throughout this specification to "one embodiment", "an embodiment", or "a specific embodiment" means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, appearances of the phrase "in one embodiment" or "in an embodiment" are not necessarily referring to the same embodiment. Furthermore, the described features, structures, or characteristics can be combined in any suitable manner in one or more embodiments. In addition, the terms "a" or "an", as used herein, mean "one or more" unless otherwise clearly indicated. Also, as used herein, the term "or" means "and / or" unless otherwise clearly indicated.

[0020] Definitions of standard chemical terminology can be found in reference works, including Carey and Sundberg "ADVANCED ORGANIC CHEMISTRY 4TH ED." Vols. A (2000) and B (2001), Plenum Press, New York. Unless otherwise indicated, conventional methods of the art are employed in practicing the present disclosure, such as mass spectroscopy, NMR, IR and UV / VIS spectroscopy and pharmacological methods. Unless specific definitions are provided, the nomenclature utilized in connection with the description herein is consistent with that employed in the relevant art. Standard techniques can be used for chemical synthesis, chemical analysis, pharmaceutical formulation, and delivery, and treatment of patients. For example, reactions and purification can be performed according to the manufacturers' instructions or according to published procedures in the literature. In general, the techniques and procedures can be performed according to conventional methods well known in the art in the light of the disclosure herein. In the present description, groups and substituents thereof can be selected by one skilled in the art to provide stable moieties and compounds.

[0021] When a certain variable is mentioned in the present disclosure as "selected from the group consisting of:...", it is meant that the variable is selected from any one of the options listed after the term "consisting of", or, where possible, one or more of the options listed after the term "consisting of".

[0022] All numerical ranges expressed in the present disclosure are intended to include both the end points of the range and all integers within the range and fractions of the integers.

[0023] In addition to the foregoing, the following terms used in the specification and claims have the following meanings unless otherwise specifically indicated.

[0024] The term "halogen" means fluorine, chlorine, bromine or iodine.

[0025] "Heteroalkyl" means an alkyl group, as defined below, in which one or more carbon atoms are replaced by atoms of an element such as nitrogen, oxygen or sulfur.

[0026] "Heteroalkyl" means an alkyl group, as defined below, in which one or more carbon atoms are replaced by atoms of an element such as nitrogen, oxygen or sulfur.

[0027] "Carbonyl" means a -C(=O)- group.

[0028] "Oxy" means an =O group.

[0029] "Thio" means an =S group.

[0030] "Nitro" means -NO2.

[0031] "Cyano" means -CN.

[0032] "Amino" means -NH2.

[0033] As used herein, a "subject" is a mammal, for example, a primate, a rat, a mouse, a cow, a horse, a pig, a sheep, a goat, a dog, a cat, and the like, and in particular a primate, and more specifically a human. In some embodiments, the "mammal" is selected from the group consisting of: a human; a domesticated animal, such as a laboratory animal, a household pet, or a farm animal, for example, a cat, a dog, a pig, a cow, a sheep, a goat, a horse, a rabbit; and a non-domesticated animal, such as a wild animal, and the like. The subject can be suspected of having or at risk of having a cancer such as prostate cancer, breast cancer, ovarian cancer, bladder cancer, glioblastoma, melanoma, renal cell carcinoma, mantle cell lymphoma, pancreatic cancer, hepatocellular carcinoma, endometrial carcinoma, salivary gland carcinoma, and the like, or suspected of having or at risk of having hair loss, acne, hirsutism, ovarian cysts, polycystic ovary disease, precocious puberty, spinal and bulbar muscular atrophy, age-related macular degeneration, and the like. Diagnostic methods for various cancers such as prostate cancer, breast cancer, ovarian cancer, bladder cancer, glioblastoma, melanoma, renal cell carcinoma, mantle cell lymphoma, pancreatic cancer, hepatocellular carcinoma, endometrial carcinoma, salivary gland carcinoma, and the like, and diagnostic methods for hair loss, acne, hirsutism, ovarian cysts, polycystic ovary disease, precocious puberty, spinal and bulbar muscular atrophy, or age-related macular degeneration, and clinical features of cancers such as prostate cancer, breast cancer, ovarian cancer, bladder cancer, glioblastoma, melanoma, renal cell carcinoma, mantle cell lymphoma, pancreatic cancer, hepatocellular carcinoma, endometrial carcinoma, salivary gland carcinoma, and the like, and clinical features of hair loss, acne, hirsutism, ovarian cysts, polycystic ovary disease, precocious puberty, spinal and bulbar muscular atrophy, or age-related macular degeneration are known to those of skill in the art. In some embodiments, the subject is confirmed or diagnosed as having the above-mentioned diseases.

[0034] The term "pharmaceutically acceptable" as used herein means a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the pharmaceutical active ingredient, i.e., a compound of the present disclosure or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotopically-substituted variant, polymorph, prodrug, or metabolite thereof, and is relatively nontoxic, i.e., the material can be administered to an individual without causing any undesirable biological effects or interacting in a deleterious manner with any of the components of the pharmaceutical composition in which it is contained. Pharmaceutically acceptable carriers or excipients include, but are not limited to, any adjuvant, carrier, excipient, glidant, sweetening, diluting, preservative, dye / coloring, flavor-enhancing, surfactant, wetting, dispersing, suspending, stabilizing, isotonic, solvent, or emulsifying agent that has been approved as acceptable for use in humans or domestic animals by, e.g., the U.S. Food and Drug Administration (FDA).

[0035] The term "pharmaceutical composition" refers to a preparation containing a compound of the disclosure or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotopically-substituted variant, polymorph, prodrug, or metabolite thereof, and a vehicle acceptable for delivery of a biologically (pharmacologically) active compound to a mammal (e.g., a human). The vehicle includes a pharmaceutically acceptable carrier or excipient. The purpose of a pharmaceutical composition is to facilitate administration of the active ingredient to a subject, to facilitate absorption, and to sustain action of the active ingredient in the body. Generally, a pharmaceutical composition of the disclosure contains from 0.1% to 99.5% by weight of a pharmaceutical active ingredient (i.e., a compound of the disclosure or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotopically-substituted variant, polymorph, prodrug, or metabolite thereof). In some embodiments, a pharmaceutical composition of the disclosure contains from 0.5% to 90% by weight, e.g., 1%, 1.5%, 2%, 5%, 10%, 15%, 20%, 25%, 30%, or 50% by weight, of a pharmaceutical active ingredient.

[0036] A compound of the disclosure can exist in a variety of different forms or derivatives, all of which are within the scope of the disclosure. These forms or derivatives include, for example, tautomers, stereoisomers (e.g., enantiomers, diastereomers), racemic mixtures, geometric isomers, salts, prodrugs, solvates, isotopically-substituted variants, different crystal forms or polymorphs, and metabolites (with particular reference to active metabolites).

[0037] In the disclosure, the term "pharmaceutically acceptable salt" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0038] A "pharmaceutically acceptable acid addition salt" means a salt with an inorganic or organic acid that retains the biological effectiveness of the free base and does not impart undesired toxicological effects to the subject. Inorganic acid salts include, but are not limited to, hydrochlorides, hydrobromides, sulfates, nitrates, phosphates, and the like; organic acid salts include, but are not limited to, formates, acetates, 2,2-dichloroacetates, trifluoroacetates, propionates, hexanoates, octanoates, decanoates, undecylenates, glycolates, gluconates, lactates, sebacates, adipates, glutarates, malonates, oxalates, maleates, succinates, fumarates, tartrates, citrates, palmitates, stearates, oleates, cinnamates, laurates, malates, glutamates, pyroglutamates, aspartates, benzoates, mesylates, besylates, tosylates, alginates, ascorbates, salicylates, 4-aminosalicylates, naphthalene- disulfonates, and the like. These salts can be prepared by methods known in the art.

[0039] "Pharmaceutically acceptable base addition salts" refer to salts formed with inorganic or organic bases that retain the bioavailability of the free acid without other side effects. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. Preferred inorganic salts are ammonium, sodium, potassium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, the following: primary amines, secondary amines, and tertiary amines; substituted amines, including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, choline, betaine, ethylenediamine, glucosamine, methylglucosamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins, etc. Preferred organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine. These salts can be prepared by methods known in the art.

[0040] As used herein, the term "prodrug" refers to those compounds that, after administration, will be metabolized (i.e., converted in the body) into pharmacologically active compounds of this disclosure. When the compounds of this disclosure are poorly absorbed from the gastrointestinal tract on their own, their bioavailability can be improved by formulating them as prodrugs. Examples of prodrugs of the compounds of this disclosure may include simple esters of compounds containing a carboxyl group (e.g., by reacting with C according to methods known in the art). 1-4 Esters obtained by alcohol condensation; esters of compounds containing hydroxyl groups (e.g., obtained by reacting with C according to methods known in the art). 1-4 Monocarboxylic acids, C 3-6 Esters obtained by condensation of dicarboxylic acids or their anhydrides, such as succinic anhydride or fumaric anhydride; imines of compounds containing amino groups (e.g., obtained by condensation with C according to methods known in the art). 1-4 Imines obtained by condensation of aldehydes or ketones; urethanes of compounds containing amino groups, such as those esters described by Leu et al. (J. Med. Chem., 42: 3623-3628 (1999)) and Greenwald et al. (J. Med. Chem., 42: 3657-3667 (1999)); aldol acetals or ketal acetals of compounds containing hydroxyl groups (e.g., those acetals obtained by condensation with chloromethyl methyl ether or chloromethyl ethyl ether according to methods known in the art).

[0041] As used herein, the term "solvate" refers to an aggregate that comprises one or more molecules of a compound of the present disclosure with one or more molecules of solvent. The solvent can be water, in which case the solvate can be a hydrate. Alternatively, the solvent can be an organic solvent. Thus, the compounds of the present disclosure can exist as a hydrate, including a monohydrate, dihydrate, hemihydrate, sesquihydrate, trihydrate, tetrahydrate and the like, as well as the corresponding solvated forms. The compounds of the present disclosure can be true solvates, while in other cases, the compounds of the present disclosure can merely retain a mixture of undefined water or water plus some undefined solvent.

[0042] Herein, "stereoisomers" refer to compounds which have the same atomic constitution but differ in the arrangement of the atoms in space. The present disclosure will encompass all such stereoisomers and mixtures thereof.

[0043] When the compounds of the present disclosure contain an olefinic double bond, the compounds of the present disclosure are intended to include both E- and Z- geometric isomers, unless otherwise noted.

[0044] "tautomers" refer to isomers that differ in the protonation of electronegative atoms, such as nitrogen, oxygen, or sulfur. All tautomeric forms of the compounds of the present disclosure are intended to be within the scope of the present disclosure.

[0045] The compounds of the present disclosure, or pharmaceutically acceptable salts thereof, can contain one or more chiral carbon atoms and thus can give rise to enantiomers, diastereomers, and other stereoisomeric forms. Each chiral carbon atom can be defined, based on its stereochemistry, as either an (R)- or (S)-. The present disclosure is intended to include all possible isomers, as well as their racemic and optically pure forms. The preparation of the compounds of the present disclosure can select a racemic, diastereomeric, or enantiomeric form as a starting material or intermediate. The optically active isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as crystallization and chromatography on chiral supports.

[0046] Conventional techniques for preparing / separating individual isomers include chiral synthesis from suitable optically pure precursors, or resolution of racemic mixtures (or racemic mixtures of salts or derivatives) using, for example, chiral high-performance liquid chromatography (HPLC). See, for example, GeRald Gübitz and Martin G. Schmid (Eds.), ChiRal SepaRations, Methods and Protocols, Methods in Molecular Biology, Vol. 243, 2004; AMStalcup, ChiRal SepaRations, Annu. Rev. Anal. Chem. 3: 341-63, 2010; Fumiss et al. (eds.), VOGEL'S ENCYCLOPEDIA OF PRACTICAL ORGANIC CHEMISTRY. sup. TH ED., Longman Scientific and Technical Ltd., Essex, 1991, 809-816; Heller, Acc. Chem. Res. 1990, 23, 128, the contents of which are incorporated herein by reference in their entirety.

[0047] This disclosure also includes all suitable isotopic substitutes (or isotopic variants) of the compounds of this disclosure or pharmaceutically acceptable salts thereof. Isotopic variants of the compounds of this disclosure or pharmaceutically acceptable salts thereof are defined as those in which at least one atom is replaced by an atom having the same atomic number but a different atomic mass than that commonly found in nature. Isotopes that can be incorporated into the compounds of this disclosure and pharmaceutically acceptable salts thereof include, but are not limited to, isotopes of H, C, N, and O, for example… 2 H, 3 H, 11 C 13 C 14 C 15 N、 17 O、 18 O、 35 S, 18 F, 36 Cl and 125 I. Isotopic variants of the compounds described in this disclosure or of their pharmaceutically acceptable salts can be prepared using conventional techniques with appropriate isotopic variants of suitable reagents.

[0048] Unless otherwise specified, the wavy lines on each structural formula or group generally indicate the position where the structural formula or group is connected to other parts of the compound.

[0049] As used herein, the terms "crystal form," "crystalline form," and "polymorph" are used interchangeably and refer to the crystal structure in which a compound (or a salt, solvate, or other derivative thereof such as a prodrug or metabolite) can crystallize in different crystal packing arrangements (all having the same elemental composition). Different crystal forms of a compound often have different X-ray diffraction patterns, infrared spectra, melting points, density hardness, crystal shape, optical and electrical properties, stability, and solubility. The dominant crystal form can be influenced by the recrystallization solvent, the rate of crystallization, storage temperature, or other factors. Polymorphs of a compound can be prepared by crystallization under different conditions.

[0050] As used herein, the terms "metabolite" and "active metabolite" are used interchangeably and refer to a derivative produced by the metabolic processes in a subject's body from a parent pharmaceutical active ingredient that also has pharmacological activity. For example, such metabolites can be produced by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, etc. of the administered compound or salt or prodrug.

[0051] As used herein, "preventing" refers to preventing the disease or condition from occurring in a mammal (preferably a human), in particular, when such mammal is predisposed to the condition but has not yet been diagnosed as having it, or to preventing a disease or condition that is already in remission from recurring in a mammal (preferably a human).

[0052] As used herein, "treatment" covers the treatment of a disease or condition of interest in a mammal (preferably a human) that has the disease or condition of interest, and includes one or more of the following: (i) inhibiting the disease or condition, i.e., arresting its development; (ii) relieving the disease or condition, i.e., causing the disease or condition to regress; and (iii) relieving the symptoms resulting from the disease or condition, i.e., relieving pain without addressing the underlying disease or condition.

[0053] "Therapeutically effective amount" means an amount effective, at dosages and for periods of time necessary to achieve the desired therapeutic result (to some extent alleviation of one or more of the symptoms of the disease or condition being treated, such as reduced tumor size, increased lifespan or increased life expectancy). A therapeutically effective amount of a compound can vary according to factors such as the disease state, age, sex, and weight of the subject, and the ability of the compound to elicit a desired response in the subject. Dosage regimens can be adjusted to provide the optimum therapeutic response. A therapeutically effective amount is also one in which any toxic or detrimental effects of the compound are outweighed by the therapeutically beneficial effects. A "prophylactically effective amount" refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result (such as preventing occurrence of disease in a subject at risk thereof and preventing recurrence of disease in a subject who has already been treated for the disease). Generally, a prophylactic dose will be administered in the early stages, prior to or at the first signs of disease, in a subject so that the prophylactically effective amount can be less than the therapeutically effective amount. Techniques for

[0054] The terms "administering," "administered," "administration," and the like, as used herein, refer to a method of delivering a compound or pharmaceutical composition to the desired site of biological action. Methods of administration well known in the art can be used with the present disclosure. These methods include, but are not limited to, oral administration, transduodenal administration, parenteral administration (including intrapulmonary, intranasal administration; intrathecal, intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical administration, and transrectal administration. Those of skill in the art are aware of techniques for administering the compounds and methods described herein, for example, those discussed in Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pa. In preferred embodiments, the compounds of the present disclosure, pharmaceutically acceptable salts, enantiomers, diastereomers, tautomers, solvates, isotopically substituted, polymorphs, prodrugs, or metabolites thereof, or pharmaceutical compositions thereof, are administered orally.

[0055] Pharmacological Basis of Therapeutics, current ed.; Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pa. In preferred embodiments, the compounds of the present disclosure, pharmaceutically acceptable salts, enantiomers, diastereomers, tautomers, solvates, isotopically substituted, polymorphs, prodrugs, or metabolites thereof, or pharmaceutical compositions thereof, are administered orally.

[0056] As used herein, "combination," "pharmaceutical combination," "combined use," or "co- treatment" refers to administration of more than one active ingredient to a patient as part of a method of treatment, including fixed and non-fixed combinations of active ingredients, and combinations of two or more different treatment modalities. The term "fixed combination" means that at least one compound described herein and at least one additional active ingredient are administered to a patient as a single entity or in a single dosage form. The term "non-fixed combination" means that at least one compound described herein and at least one additional active ingredient are administered to a patient as separate entities either simultaneously, concurrently or sequentially with variable intervening time periods. These also apply to cocktail therapies, e.g., administration of three or more active ingredients.

[0057] For the avoidance of doubt, in the present disclosure, compounds drawn with a wedge bond (e.g., Compound 1) are single-configuration compounds as determined by absolute stereochemistry.

[0058] III. Uses

[0059] The YAP / TAZ-TEAD interaction inhibitor suitable for use in the present application can be various YAP / TAZ-TEAD interaction inhibitors well known in the art. In some embodiments, the present application uses a compound disclosed in WO 2023 / 155927 as the YAP / TAZ-TEAD interaction inhibitor. In some embodiments, the present application uses Compound 1 represented by the following formula or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotopically substituted, polymorph, prodrug, or metabolite thereof as the YAP / TAZ-TEAD interaction inhibitor:

[0060] The present disclosure also includes pharmaceutically acceptable salts, enantiomers, diastereomers, tautomers, solvates, isotopically substituted, polymorphs, prodrugs, or metabolites of Compound 1 described above.

[0061] III. Uses

[0062] The YAP / TAZ-TEAD interaction inhibitor has tumor treatment activity, and the therapeutic effect of the combination of the YAP / TAZ-TEAD interaction inhibitor and the taxane drug is superior to that of the YAP / TAZ-TEAD interaction inhibitor or the taxane drug alone. Therefore, the present disclosure provides the use of the combination of the YAP / TAZ-TEAD interaction inhibitor and the taxane drug in the preparation of a medicament for the treatment and / or prevention of cancer.

[0063] In some embodiments, the YAP / TAZ and TEAD interaction inhibitor described herein is Compound 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotopically-substituted variant, polymorph, prodrug, or metabolite thereof, as shown in the following formula:

[0064] In some embodiments, the taxane drug comprises a taxane compound, and a drug release precursor thereof. The taxane compound is selected from one or more of taxane, paclitaxel (Taxol®), docetaxel (Taxotere®), cabazitaxel (Jevtana®), paclitaxel liposome (Abraxane®), and albumin-bound paclitaxel (nab-paclitaxel). Preferably, the taxane compound is paclitaxel. In some embodiments, the drug release precursor is a conjugated drug with a taxane compound as a drug load. Preferably, the drug release precursor is a cabazitaxel-antibody conjugated drug.

[0065] In some embodiments, the cancer is selected from lung cancer, Breast Cancer, Gastric Cancer, Head and Neck Cancer, pancreatic cancer, sarcoma, lung cancer, esophageal cancer, intestinal cancer, cholangiocarcinoma, liver cancer, peritoneal cancer, cancer of the reproductive system, adenocarcinoma, glioma, Non-Small Cell Lung Cancer (NSCLC), triple negative breast cancer, head and neck squamous cell carcinoma, endometrial cancer, Fallopian Tube Carcinoma, Ovarian Cancer, germ cell cancer, nasopharyngeal cancer, oral cancer, metastatic pancreatic adenocarcinoma, angiosarcoma, metastatic breast cancer, pancreatic adenocarcinoma, endometrial cancer, uterine cancer, recurrent endometrial cancer, cervical cancer, non-small cell lung cancer, AIDS-related Kaposi's sarcoma, high-grade glioma, HEGF2-negative breast cancer, metastatic HER2-negative breast cancer, triple negative breast cancer, primary peritoneal low-grade serous adenocarcinoma, HER2-negative breast cancer, HR-positive / HER2-negative breast cancer, advanced triple negative breast cancer, metastatic triple negative breast cancer, choriocarcinoma, endodermal sinus tumor, non-seminomatous germ cell tumor, seminoma, early stage breast cancer, esophageal adenocarcinoma, gastroesophageal junction adenocarcinoma, HER2-positive esophageal cancer, borderline ovarian mucinous tumor, mucinous cystadenocarcinoma, Brenner tumor, ovarian endometrioid carcinoma, malignant mixed tumor, mucinous adenocarcinoma, ovarian mixed epithelial carcinoma, ovarian mucinous adenocarcinoma, ovarian serous adenocarcinoma, primary peritoneal serous adenocarcinoma, urothelial carcinoma, undifferentiated ovarian carcinoma, recurrent ovarian cancer, advanced urothelial carcinoma, primary peritoneal cancer, colorectal cancer, platinum-resistant primary peritoneal cancer, vulvar tumor, malignant epithelial tumor, locally advanced malignant solid tumor, unresectable malignant solid tumor, metastatic solid tumor, appendiceal tumor, small cell lung cancer, epithelioid sarcoma, advanced breast cancer, EGFR-mutated non-small cell lung cancer, neoplastic process, bone metastatic cancer, gastric adenocarcinoma, metastatic adenocarcinoma, small bowel cancer, urethral tumor, bladder cancer, recurrent small bowel cancer, metastatic non-squamous non-small cell lung cancer, metastatic cholangiocarcinoma, metastatic hepatocellular carcinoma, unresectable hepatocellular carcinoma, unresectable intrahepatic cholangiocarcinoma, human papillomavirus-associated head and neck tumor, neutropenia, peripheral nervous system disorder, esophageal squamous cell carcinoma, advanced gastric cancer, high-grade fallopian tube serous adenocarcinoma, ovarian high-grade serous adenocarcinoma, platinum-resistant fallopian tube cancer, primary peritoneal high-grade serous adenocarcinoma, refractory primary peritoneal serous adenocarcinoma, locally advanced pancreatic adenocarcinoma, endometrioid adenocarcinoma, anal canal cancer, anal squamous cell carcinoma, squamous cell lung cancer, head and neck squamous cell carcinoma, gastroesophageal junction cancer, metastatic esophageal cancer, metastatic gastroesophageal junction adenocarcinoma, recurrent esophageal squamous cell carcinoma, recurrent gastroesophageal junction adenocarcinoma, fallopian tube clear cell adenocarcinoma, ovarian clear cell adenocarcinoma, recurrent uterine corpus cancer,one or more of recurrent laryngeal squamous cell carcinoma, metastatic head and neck squamous cell carcinoma, hypopharyngeal squamous cell carcinoma, oral squamous cell carcinoma recurrence, oropharyngeal squamous cell carcinoma, renal cell carcinoma, ER-negative breast cancer, progesterone receptor-negative breast cancer, unresectable non-small cell lung cancer, recurrent head and neck squamous cell carcinoma, HER2-positive metastatic breast cancer, recurrent nasopharyngeal carcinoma, metastatic castration-resistant prostate cancer, metastatic prostate cancer, refractory malignant germ cell tumor, gastroesophageal junction malignancy, platinum-resistant ovarian cancer, castration-resistant prostate cancer, male breast tumor, metastatic salivary gland carcinoma, salivary gland carcinoma recurrence, bladder urothelial carcinoma, locally advanced gastroesophageal junction adenocarcinoma, non-muscle invasive bladder tumor, primary peritoneal endometrioid adenocarcinoma, refractory ovarian cancer, fallopian tube disease, recurrent solid tumor, advanced malignant solid tumor, recurrent platinum-resistant primary peritoneal cancer, and squamous cell carcinoma. In some embodiments, the cancer is triple-negative breast cancer.

[0066] IV. Pharmaceutical compositions, kits, and uses thereof

[0067] The present disclosure found that YAP / TAZ and TEAD interaction inhibitors in combination with taxanes have excellent effects in treating cancer, and provided a pharmaceutical composition comprising a YAP / TAZ and TEAD interaction inhibitor, a taxane, and a pharmaceutically acceptable carrier. In some embodiments, the YAP / TAZ and TEAD interaction inhibitor and the taxane are as described in any of the embodiments herein.

[0068] A "pharmaceutically acceptable carrier" refers to one or more compatible solid or liquid filler substances or gel materials that are suitable for human use and must be of sufficient purity and sufficiently low toxicity. "Compatible" here means that the components of the composition are capable of being commingled with the compound of the present disclosure, and with each other, without any significant adverse effects, such as an adverse reaction that would preclude useful co-administration. Examples of suitable pharmaceutically acceptable carriers are cellulose and its derivatives (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyhydric alcohols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as Tween), wetting agents (such as sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, and the like.

[0069] The mode of administration of the YAP / TAZ and TEAD interaction inhibitor, the taxane, or the pharmaceutical composition of the present disclosure is not particularly limited, and representative modes of administration include, but are not limited to, oral or parenteral (intravenous, intramuscular, or subcutaneous).

[0070] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is admixed with at least one inert excipient (or carrier) such as sodium citrate or dicalcium phosphate, or with such excipients as (a) fillers or extenders, e.g., starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, e.g., hydroxymethylcellulose, alginic acid, gelatin, polyvinylpyrrolidone, sucrose, and acacia; (c) humectants, e.g., glycerol; (d) disintegrating agents, e.g., agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solution retarders, e.g., paraffin; (f) absorption accelerators, e.g., quaternary ammonium compounds; (g) moisturizing agents, e.g., glycerol and sorbitol; (h) respiration accelerators, e.g., high molecular weight polyethylene glycols; and (i) lubricants, e.g., talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets, and pills, the dosage forms also can comprise buffering agents.

[0071] Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, e.g., enteric coatings and other materials well known in the art. They can optionally contain opacifying agents, and can also be of a composition that they release the active compound or compounds in a certain part of the digestive tract. Examples of embedding compositions that can be used are polymeric substances and waxes. The active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.

[0072] Liquid dosage forms for oral administration include pharmaceutically-acceptable emulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compounds, the liquid dosage forms can contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, as, for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, and the like, as well as mixtures thereof.

[0073] Besides such inert diluents, the composition can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0074] Suspensions, in addition to the active compounds, can contain suspending agents, as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, and sodium carbomate, among others.

[0075] Compositions for parenteral injection can include physiologically acceptable, sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and nonaqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0076] In some embodiments, the YAP / TAZ and TEAD interaction inhibitor is administered at a dose of 5-60 mg / kg, preferably 15-30 mg / kg.

[0077] In some embodiments, the taxane is administered at a dose that is its conventional dose, for example, at a dose of 2.5-30 mg / kg, preferably 10-20 mg / kg.

[0078] In some embodiments, the pharmaceutical composition comprises (i) an oral formulation comprising a YAP / TAZ and TEAD interaction inhibitor; and (ii) an injection formulation comprising a taxane. In the oral formulation, the pharmaceutically acceptable carrier can be selected from HP-β-CD and water, and the HP-β-CD can enhance the solubility of the YAP / TAZ and TEAD interaction inhibitor in water, facilitating the delivery of the YAP / TAZ and TEAD interaction inhibitor in vivo. In the oral formulation, the concentration of the YAP / TAZ and TEAD interaction inhibitor can be 1-3 mg / mL, for example, 2 mg / mL. In the injection formulation, the pharmaceutically acceptable carrier can be selected from physiological saline. In the injection formulation, the concentration of the taxane can be 1-3 mg / mL, for example, 1.5 mg / mL.

[0079] In some embodiments, the pharmaceutical composition of the present disclosure further comprises other known anticancer agents in addition to the YAP / TAZ and TEAD interaction inhibitor and the taxane of the present disclosure, including but not limited to chemotherapeutic agents, for example, mitotic inhibitors such as vinca alkaloids (e.g., vincristine, vinblastine, vinorelbine or vinflunine), other anticancer agents such as metal platinum complexes (e.g., cisplatin, carboplatin or oxaliplatin), antimetabolites (e.g., pyrimidine antagonists such as 5-fluorouracil, 5-fluoro-2-4(lH,3H)-pyrimidinedione (5FU), gemcitabine), hormonal antitumor drugs (e.g., flutamide), tumor immunotherapeutic drugs (e.g., anti-PDl antibody), and the like.

[0080] The present disclosure also provides the use of the pharmaceutical composition of the present disclosure in the preparation of a medicament for the treatment and / or prevention of cancer. The cancer is as described in any of the embodiments herein.

[0081] In some embodiments, the present disclosure also provides a kit comprising a YAP / TAZ and TEAD interaction inhibitor and a taxane of any of the embodiments described herein, or a pharmaceutical composition of the present disclosure. In the kit, the YAP / TAZ and TEAD interaction inhibitor and the taxane can be packaged separately, which can be provided in the kit in each independent pharmaceutical composition for sequential or simultaneous administration. In some embodiments, the YAP / TAZ and TEAD interaction inhibitor and the taxane are contained in the same pharmaceutical composition for simultaneous administration.

[0082] VI. Methods of Treatment

[0083] The present disclosure provides a method of treating or preventing cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a YAP / TAZ and TEAD interaction inhibitor and a taxane of the present disclosure, or a pharmaceutical composition of the present disclosure. The YAP / TAZ and TEAD interaction inhibitor, the taxane, and the cancer are as described in any of the embodiments herein.

[0084] In some embodiments, the YAP / TAZ and TEAD interaction inhibitor and the taxane are administered simultaneously, sequentially or separately.

[0085] The YAP / TAZ and TEAD interaction inhibitor and the taxane of the present disclosure, or a pharmaceutical composition of the present disclosure, can be administered alone or in combination with other known anti-cancer agents.

[0086] In some embodiments, the YAP / TAZ and TEAD interaction inhibitor and the taxane, or a pharmaceutical composition of the present disclosure, are administered simultaneously, sequentially or separately in combination with one or more anti-cancer agents selected from chemotherapeutic agents, such as mitotic inhibitors, e.g., vinca alkaloids (e.g., vincristine, vinblastine, vinorelbine or vinflunine), other anticancer agents such as metal platinum complexes (e.g., cisplatin, carboplatin or oxaliplatin), antimetabolites (e.g., pyrimidine antagonists such as 5-fluorouracil, 5-fluoro-2-4(lH,3H)-pyrimidine-dione (5FU) or gemcitabine), hormonal antineoplastic agents (e.g., flutamide), and the like.

[0087] In some embodiments, the YAP / TAZ and TEAD interaction inhibitor and the taxane of the present disclosure, or a pharmaceutical composition of the present disclosure, are used in combination with conventional radiotherapy.

[0088] Advantages of the present disclosure include:

[0089] The combination of YAP / TAZ and TEAD interaction inhibitor (e.g., Compound 1) and taxane drugs for treating cancer has more significant efficacy than the use of paclitaxel alone.

[0090] The present application is further illustrated by the following specific examples. It should be understood that these examples are included merely to illustrate the present application and should not be considered limiting of the scope of the application. Unless otherwise indicated, the methods of preparing the examples below generally follow conventional procedures or those described in the examples. Unless otherwise indicated, all percentages and parts are by weight.

[0091] Example 1: In vivo therapeutic effect of the combination of Compound 1 and paclitaxel on human triple-negative breast cancer MDA-MB-231 cell subcutaneous xenograft

[0092] The chemical structure of Compound 1 used in this example is as follows:

[0093] which is Compound 124 disclosed in WO 2023 / 155927.

[0094] The experimental methods of this example are as follows:

[0095] (1) Prepare 6-8-week-old female BALB / C nude mice.

[0096] (2) Take human breast cancer MDA-MB-231 cells, culture in vitro, and use DMEM medium added with 10% fetal bovine serum and double antibiotics (penicillin and streptomycin) to culture the cells. Culture in a 37°C 5% CO2 incubator. Perform routine digestion treatment with trypsin, and when the cells are in the exponential growth phase, the saturation degree is 80%-90%, and the number reaches the requirement, collect the cells, count, and resuspend with PBS solution.

[0097] (3) Subcutaneously inoculate 1x 10 7 MDA-MB-231 cells (0.2 mL in volume after resuspension) on the right back of the mice prepared in (1). When the average volume of the subcutaneous tumor reaches 164 mm 3 on the 3rd day after cell inoculation, divide the mice into 4 groups, 6 mice in each group. The grouping and dosing regimens are shown in Table 1, and the preparation method of the test samples is shown in Table 2.

[0098] Table 1: Grouping and dosing regimens

[0099] Table 2: Preparation method of test samples Note: Mix the test samples thoroughly before administration.

[0100] (4) Tumor diameter was measured with vernier caliper three times a week. The experiment was ended on day 29, and tumor volume was calculated according to tumor diameter.

[0101] The formula of tumor volume was: V=0.5a x b 2 , a and b represent long diameter and short diameter of tumor respectively.

[0102] The results of tumor volume at different time points were shown in Figure 1, and the statistical results of tumor volume at the end of experiment were shown in Table 3.

[0103] Table 3 Note:

[0104] a. Mean ± SEM;

[0105] b. p value was analyzed by T-Test according to tumor volume of each animal in different groups, taking control group as control;

[0106] c. p value was analyzed by T-Test according to tumor volume of each animal in different groups, taking compound 1 group as control;

[0107] d. p value was analyzed by T-Test according to tumor volume of each animal in different groups, taking paclitaxel group as control.

[0108] At the end of experiment, the tumor volume of compound 1 experimental group and paclitaxel experimental group was significantly smaller than that of control group, and the tumor volume of compound 1 and paclitaxel combination group was significantly lower than that of control group, compound 1 experimental group and paclitaxel experimental group, indicating that the combination therapy of compound 1 and paclitaxel obtained more significant efficacy than paclitaxel monotherapy in human breast cancer model.

Claims

1. Use of a YAP / TAZ and TEAD interaction inhibitor and a taxane drug in the preparation of a medicament for treating and / or preventing cancer.

2. Use according to claim 1, characterized in that, The YAP / TAZ-TEAD interaction inhibitor is Compound 1 or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotopically-substituted, polymorph, prodrug, or metabolite thereof:

3. Use according to claim 1, characterized in that, The taxane drug comprises a taxane compound selected from one or more of taxane, paclitaxel, docetaxel, cabazitaxel (Jevtana), paclitaxel liposome and albumin-bound paclitaxel, and a drug release precursor thereof.

4. Use according to claim 3, characterized in that, The drug release precursor is a conjugated drug with the taxane compound as a drug load.

5. The use according to claim 3, characterized in that, The taxane compound is paclitaxel; and / or, the drug release precursor is a cabazitaxel-antibody conjugated drug.

6. The use according to claim 1, characterized in that, The cancer is selected from the group consisting of lung cancer, breast cancer, gastric cancer, head and neck cancer, pancreatic cancer, sarcoma, lung cancer, esophageal cancer, intestinal cancer, cholangiocarcinoma, liver cancer, peritoneal cancer, reproductive system cancer, adenocarcinoma, glioma, non-small cell lung cancer, triple negative breast cancer, head and neck squamous cell carcinoma, endometrial cancer, fallopian tube cancer, ovarian cancer, germ cell cancer, nasopharyngeal cancer, oral cancer, metastatic pancreatic adenocarcinoma, angiosarcoma, metastatic breast cancer, pancreatic adenocarcinoma, endometrial cancer, uterine cancer, recurrent endometrial cancer, cervical cancer, non-small cell lung cancer, AIDS-related Kaposi's sarcoma, high-grade glioma, HEGF2-negative breast cancer, metastatic HER2-negative breast cancer, triple negative breast cancer, primary peritoneal low-grade serous adenocarcinoma, HER2-negative breast cancer, HR-positive / HER2-negative breast cancer, advanced triple negative breast cancer, metastatic triple negative breast cancer, choriocarcinoma, endodermal sinus tumor, non-seminomatous germ cell tumor, seminoma, early stage breast cancer, esophageal adenocarcinoma, gastroesophageal junction adenocarcinoma, HER2-positive esophageal cancer, borderline ovarian mucinous tumor, mucinous cystadenocarcinoma, Brenner tumor, ovarian endometrioid carcinoma, malignant mixed tumor, mucinous adenocarcinoma, ovarian mixed epithelial carcinoma, ovarian mucinous adenocarcinoma, ovarian serous adenocarcinoma, primary peritoneal serous adenocarcinoma, urothelial carcinoma, undifferentiated ovarian carcinoma, recurrent ovarian cancer, advanced urothelial carcinoma, primary peritoneal cancer, colorectal cancer, platinum-resistant primary peritoneal cancer, vulvar tumor, malignant epithelial tumor, locally advanced malignant solid tumor, unresectable malignant solid tumor, metastatic solid tumor, appendix tumor, small cell lung cancer, epithelioid sarcoma, advanced breast cancer, EGFR-mutated non-small cell lung cancer, tumor process, bone metastatic cancer, gastric adenocarcinoma, metastatic adenocarcinoma, small intestine cancer, urethral tumor, bladder cancer, recurrent small intestine cancer, metastatic non-squamous non-small cell lung cancer, metastatic cholangiocarcinoma, metastatic hepatocellular carcinoma, unresectable hepatocellular carcinoma, unresectable intrahepatic cholangiocarcinoma, human papillomavirus-related head and neck tumor, neutropenia, peripheral nervous system disease, esophageal squamous cell carcinoma, advanced gastric cancer, high-grade fallopian tube serous adenocarcinoma, ovarian high-grade serous adenocarcinoma, platinum-resistant fallopian tube cancer, primary peritoneal high-grade serous adenocarcinoma, refractory primary peritoneal serous adenocarcinoma, locally advanced pancreatic adenocarcinoma, endometrioid adenocarcinoma, anal canal cancer, anal squamous cell carcinoma, squamous cell lung cancer, head and neck squamous cell carcinoma, gastroesophageal junction cancer, metastatic esophageal cancer, metastatic gastroesophageal junction adenocarcinoma, recurrent esophageal squamous cell carcinoma, recurrent gastroesophageal junction adenocarcinoma, fallopian tube clear cell adenocarcinoma, ovarian clear cell adenocarcinoma, recurrent corpus cancer, recurrent laryngeal squamous cell carcinoma, metastatic head and neck squamous cell carcinoma, hypopharyngeal squamous cell carcinoma, oral squamous cell carcinoma recurrence, oropharyngeal squamous cell carcinoma, renal cell carcinoma, ER-negative breast cancer, progesterone receptor-negative breast cancer, unresectable non-small cell lung cancer, recurrent head and neck squamous cell carcinoma, HER2-positive metastatic breast cancer, recurrent nasopharyngeal carcinoma, metastatic castration-resistant prostate cancer, metastatic prostate cancer,one or more of refractory malignant germ cell tumors, gastroesophageal junction malignancies, platinum-resistant ovarian cancer, castration-resistant prostate cancer, male breast tumors, metastatic salivary gland carcinoma, salivary gland cancer recurrence, bladder urothelial cancer, locally advanced gastroesophageal junction adenocarcinoma, non-muscle invasive bladder tumors, primary peritoneal endometrioid adenocarcinoma, refractory ovarian cancer, fallopian tube disease, recurrent solid tumors, advanced malignant solid tumors, recurrent platinum-resistant primary peritoneal cancer, and squamous cell carcinoma.

7. A pharmaceutical composition, characterized by, The pharmaceutical composition comprises the YAP / TAZ and TEAD interaction inhibitor, the taxane drug and a pharmaceutically acceptable carrier.

8. The pharmaceutical composition of claim 7, wherein, The pharmaceutical composition comprises (i) an oral preparation containing the YAP / TAZ and TEAD interaction inhibitor; and (ii) an injection containing the taxane drug.

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