WO2024220470A1

WO2024220470A1 - Tead inhibitors and uses thereof in the treatment of proliferative disorders

Info

Publication number: WO2024220470A1
Application number: PCT/US2024/024884
Authority: WO
Inventors: Mihir RAJURKAR; Nathan Young
Original assignee: Ikena Oncology Inc
Current assignee: ImageneBio Inc
Priority date: 2023-04-17
Filing date: 2024-04-17
Publication date: 2024-10-24
Anticipated expiration: 2025-10-17

Abstract

The present disclosure provides a TEAD inhibitor, and methods of use thereof.

Description

TEAD INHIBITORS AND USES THEREOF CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims the benefit of priority to United States Provisional Patent Application serial number 63/496,517, filed April 17, 2023, the contents of which are herein incorporated by reference in their entirety. TECHNICAL FIELD OF THE INVENTION [0002] The present disclosure relates to TEAD inhibitor N-methyl-3-(1-methyl-1H-imidazol- 4-yl)-4-((4-(trifluoromethyl)benzyl)amino)benzenesulfonamide (Compound A), and methods of use thereof. BACKGROUND OF THE INVENTION [0003] Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) are transcriptional co-activators of the Hippo pathway network and regulate cell proliferation, migration, and apoptosis. Inhibition of the Hippo pathway promotes YAP/TAZ translocation to the nucleus, wherein YAP/TAZ interact with TEAD transcription factors and coactivate the expression of target genes and promote cell proliferation. Hyperactivation of YAP and TAZ and/or mutations in one or more members of the Hippo pathway network have been implicated in numerous cancers. SUMMARY OF THE INVENTION [0004] It has been found that TEAD inhibitor N-methyl-3-(1-methyl-1H-imidazol-4-yl)-4-((4- (trifluoromethyl)benzyl)amino)benzenesulfonamide (Compound A) promotes vestigial like 4 peptide (VGLL4) binding to TEAD1, which functions as a transcriptional repressor and suppress cancer cell growth. [0005] Accordingly, provided herein are methods for determining the efficacy of treatments using Compound A and/or selecting a patient for application or administration of a treatment comprising Compound A. Such methods comprise, in part, methods of identifying patients having elevated VGLL4 levels and/or TEAD1 levels, and methods for treating patients having elevated VGLL4 levels and/or TEAD1 levels using Compound A. Page 1 of 49 BUSINESS31347208.1 396661-058WO (209307) [0006] In one aspect, the present disclosure provides a method of identifying or selecting a patient having an elevated VGLL4 level and/or TEAD1 level, comprising measuring the VGLL4 level and/or TEAD1 level in a tissue sample of a patient, and selecting a patient having an elevated VGLL4 level and/or TEAD1 level in the tissue sample. [0007] In another aspect, provided herein is a method of treating a proliferative disorder in a patient having or identified as having an elevated VGLL4 level and/or TEAD1 level, for example, as determined using a method described herein, comprising administering to the patient a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof. [0008] In another aspect, the present disclosure provides a method of treating a patient having a proliferative disorder, comprising selecting a patient having an elevated VGLL4 level and/or TEAD1 level, for example, using a method as described herein, and administering to the patient a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof. [0009] In some embodiments, a method provided herein comprises administering daily to a patient about 25 – 1200 mg of Compound A, or a pharmaceutically acceptable salt thereof. In some embodiments, a method provided herein comprises administering once daily, or twice daily, or thrice daily, or four-times daily, Compound A, or a pharmaceutically acceptable salt thereof. [0010] In some embodiments, a proliferative disorder is a cancer having an elevated VGLL4 level and/or TEAD1 level in the cancer tissue. In some embodiments, a cancer is selected from those as described herein. In some embodiments, the cancer is an NF2-deficient solid tumor, including, but not limited to, mesothelioma, meningioma, cholangiocarcinoma, thymoma, NSCLC, HCC, and others. In some embodiments, the NF2-deficient solid tumor has NF2 loss-of- function mutations. In some embodiments, the NF2-deficient solid tumor has NF2 copy number loss. In some embodiments, the cancer is epithelioid hemangioendothelioma (EHE). In some embodiments, the cancer is epithelioid hemangioendothelioma (EHE) with a TAZ-CAMTA1 or YAP1-TFE3 gene fusion. In some embodiments, the cancer is a solid tumor with a YAP1 or TAZ gene fusion. BRIEF DESCRIPTION OF FIGURES [0011] FIG.1 depicts that TEADs function in two opposing states, depending on the binding partner: i) as an activator with YAP1 or TAZ (TEAD palmitoylation dependent); and ii) as a repressor with VGLL4 (palmitoylation independent): VGLL4 repression is TEAD dependent Page 2 of 49 BUSINESS31347208.1 396661-058WO (209307) (TEAD-binding deficient mutants do not repress transcription), and VGLL4 competes with YAP1/TAZ to inhibit transcription. Chan P et al. Nat. Chem. Bio. 2016; Li Q et al., Cell Stem Cell.2020; Zhang W et al., Cell Res.2014. [0012] FIG.2 depicts: binding of Compound A or a pan-TEAD inhibitor to TEAD1-4 using a BODIPY-palmitate Fluorescence Polarization (FP) competition assay (a) or a NanoBRET assay (b); (c) blocking of alkyl-palmitoyl-CoA binding by Compound A or a pan-TEAD inhibitor to recombinant TEAD1-4 YAP1-binding domain using a click chemistry assay; (d) the relative potency of Compound A or a pan-TEAD inhibitor in biochemical and cellular assays; and (e) structural representation of TEAD1 and TEAD4 palmitoylation pockets highlighting rationale for TEAD1 selective binding of Compound A. [0013] FIG.3 depicts: (a) anti-tumor activity in the NF2 deficient mesothelioma tumor NCI- H226 grown as a xenograft in mice; (b) morbidity and histopathology in rats and monkeys for Compound A and pan-TEAD inhibitor; and (c) average urinary protein-to-creatinine ratios relative to exposures in monkeys treated with Compound A or a pan-TEAD inhibitor, and average Compound A or pan-TEAD inhibitor exposures associated with different percent tumor growth inhibition (TGI) of NCI-H226 xenografts in mice (vertical line). [0014] FIG.4 depicts: (a) TEAD luciferase reporter in cells treated with TEAD1 and VGLL4 siRNAs; (b) CTGF and CYR61 expression in cells treated with TEAD1 siRNAs. [0015] FIG. 5 depicts: (a) TEAD1-YAP1 co-IP in FLAG-TEAD1 knock-in MSTO-211H treated with Compound A or a pan-TEAD inhibitor; (b) TEAD1-VGLL4 co-IP in 293T expressing FLAG-TEAD1 and HA-VGLL4 treated with Compound A or a pan-TEAD inhibitor; (c) TEAD1- VGLL4, TEAD1-TEAD4 co-IP in 293T expressing FLAG-TEAD1, V5-TEAD4 and wild-type HA-VGLL4 (VGLL4WT) or HA-VGLL4 mutated in the TDU-TEAD interaction domains (VGLL4MUT) treated with Compound A; (d) Co-crystal structure of Compound A/TEAD1 modeled with VGLL4 and TEAD4 (based on crystal structure from Jiao et al., Cancer Cell 2014). [0016] FIG.6 depicts: (a) TEAD target gene down regulation in primary mesothelioma cells treated with 2 Compound A concentrations (3x); (b) primary mesothelioma cell number change with TEAD1 siRNAs and/or Compound A; (c) images showing differential effect of Compound A +/- siTEAD1; (d) Western measuring doxycycline-induced expression of VGLL4WT or VGLL4MUT in Mero14; (e) Compound A effect on growth of Mero14 expressing doxycycline induced VGLL4WT or VGLL4MUT. Page 3 of 49 BUSINESS31347208.1 396661-058WO (209307) [0017] FIG. 7 depicts: (a) Western blot measuring CRISPR-mediated TEAD1 knockout in EGFR mutant PC9; (b) Apoptosis induction in PC9 sgTEAD1 cells treated with osimertinib or osimertinib and Compound A measured using a caspase-activated fluorescent probe; (c) Apoptosis induction in PC9 sgVGLL4 cells treated with osimertinib or osimertinib and Compound A measured using a caspase-activated fluorescent probe. [0018] FIG.8 depicts: (a) TEAD paralog expression in mesothelioma versus all other tumor types from TCGA; (b) TEAD paralog expression in primary mesothelioma cell lines (n=19), mesothelioma cell lines in DepMap and all other cell lines in DepMap; (c) TEAD paralog expression in EHE tumor samples (n=6) and all tumors in TCGA; (d) VGLL4 expression by tumor type in TCGA; (e) VGLL4 expression in EHE tumors samples (n=6), in EHE samples from GSE168493 (Seavey et al., Genes Development 2021) or in all tumors in TCGA. [0019] FIG. 9 depicts schema representing TEAD activator and transcriptional repressive states in presence or absence of Compound A. DETAILED DESCRIPTION OF THE INVENTION 1. General Description of Certain Embodiments of the Invention [0020] Compound A is a novel, synthetic, small molecule inhibitor designed to target and selectively inhibit TEAD. The TEAD family comprises 4 members or paralogs, (e.g., human TEAD1 (UniProt KB ID P28347-1), human TEAD2 (UniProtKB ID Q15562), human TEAD3 (UniProtKB ID Q99594), and human TEAD4 (UniProtKB ID Q15561) and henceforth will also be referred to collectively as TEAD or TEAD paralogs. TEAD paralogs function as the ultimate step in the Hippo signal transduction pathway by driving expression of genes involved in cell proliferation, adhesion, migration, biogenesis, angiogenesis, and apoptosis (Calses 2019). Activation of TEAD transcription depends on formation of a heterodimeric complex with either of the two key transcriptional coactivators, Yes1 associated transcriptional regulator (YAP1) or WW domain containing transcription regulator 1 (TAZ/WWTR1), as well as binding of the lipid palmitate to TEAD’s central lipid pocket (Chan 2016). TAZ is encoded by the WWTR1 gene and TAZ is used when describing either the protein or the gene, herein. [0021] When the upstream Hippo pathway is turned on, YAP1/TAZ are phosphorylated and sequestered to the cytoplasm or targeted for proteasomal degradation and TEAD paralog- dependent gene expression is reduced. On the contrary, when YAP1/TAZ are not phosphorylated, Page 4 of 49 BUSINESS31347208.1 396661-058WO (209307) the co-activators are able to translocate into the nucleus, bind TEAD transcription factors, and activate transcription of TEAD-dependent target genes (Holden 2018). In contrast, TEAD paralogs bound to VGLL4 have been shown to suppress gene expression. VGLL4 repression is TEAD dependent (TEAD-binding deficient mutants do not repress transcription), and VGLL4 competes with YAP1/TAZ to inhibit transcription. Chan P et al. Nat. Chem. Bio.2016; Li Q et al., Cell Stem Cell.2020; Zhang W et al., Cell Res.2014. [0022] The Hippo pathway is frequently mutated in human cancers, which leads to an aberrant activation of TEAD-dependent transcription (Kulkarni 2020). Genetic alterations in the Hippo pathway are linked to the etiology of many cancers, are generally associated with poor patient outcome, and drive resistance to both chemotherapies and targeted therapies. [0023] The Hippo pathway is genetically altered in approximately 10% of all cancers; however, in certain rare tumors, the genetic alterations of the Hippo pathway can be found in over 40% of cases, including malignant pleural mesothelioma (MPM), that have mutations and copy number losses associated with neurofibromin 2 (NF2) deficiency (Sato 2018). NF2 is a tumor suppressor gene that encodes merlin, a key regulator of the Hippo signaling pathway. Complete loss of the NF2 function can lead to an inability to suppress TEAD-dependent transcription, driving the expression of multiple genes leading to enhanced tumor cell growth. Malignant mesothelioma is a rare cancer in the tissue lining the lungs and is a very aggressive cancer with a poor prognosis. There are few effective treatment options for advanced unresectable malignant mesothelioma, and to date, only two treatments have been approved by the FDA for the treatment of this condition in the last 16 years. Even with a newly approved treatment in 2020, the median overall survival of these patients is 18 months, with most of the patients eventually progressing and dying from their disease. [0024] NF2 deficiency also occurs at high incidence in meningiomas, cholangiocarcinomas, thymoma, and schwannoma. Meningiomas are the most common brain tumor, accounting for 36.4% of all primary brain tumors in the United States (Ostrom 2015). Notably, multiple studies found NF2 gene aberrations in 40% to 60% of sporadic meningiomas, in addition to those that appeared alongside neurofibromatosis type 2, which is defined by NF2 germline mutations (Yuzawa 2016; Bi 2017; Harmanci 2017; Pemov 2020). Initial therapy for meningioma is surgery with or without radiation. While complete resection can be curative in most cases, no therapies have been shown to prolong progression-free or overall survival in patients with recurrent or Page 5 of 49 BUSINESS31347208.1 396661-058WO (209307) unresectable meningiomas, and there are no approved treatments for this subset of patients. [0025] Certain solid tumors have high nuclear YAP1 or TAZ protein, indicating high TEAD activation, and YAP1/TAZ gene amplification or fusion. This includes, but is not limited to, epithelioid hemangioendothelioma (EHE), where 90% of the cases are associated with TAZ- CAMTA1 gene fusion, and the other 10% of cases have YAP1-TFE3 gene fusion. In the case of EHE, localized disease is treated by organ involvement with surgery, but there is no systemic treatment approved for EHE with advanced or metastatic disease (Stacchiotti 2021). Typically, this disease is refractory to the anticancer drugs used to treat other soft tissue sarcomas. Treatment options include retrospective data on interferons, thalidomide, some small Phase 2 studies testing antiangiogenic agents like bevacizumab and pazopanib, and, more recently, use of MEK inhibitors associated with an ORR of 7% (Schuetze 2021; Stacchiotti 2021). [0026] Other solid tumors also express YAP1/TAZ gene alterations including angiosarcoma, liposarcomas, synovial sarcomas, NSCLC, cervical cancer, mesothelioma, and others (Fullenkamp 2016; Merritt 2018; Isfort 2019; Yoshida 2019; Kao 2020; Massoth 2020; Puls 2020; Schuetze 2021; Stacchiotti 2021). [0027] Hippo pathway alterations or dysregulations are associated with a subset of rare tumors with poor prognosis and limited therapeutic options, thus constituting a significant unmet medical need. Therefore, inhibiting TEAD function in these tumors targeting the Hippo pathway represents a promising strategy for developing novel anticancer therapies. [0028] Compound A is a novel synthetic small molecule inhibitor that binds to the central lipid pocket of TEAD, prevents palmitate binding, selectively inhibits the TEAD1 paralog, disrupts YAP1/TEAD1 binding and stabilizes VGLL3/TEAD1 binding, thereby shifting the equilibrium of TEAD1 towards a repressive transcriptional state, by disrupting its interaction with YAP1 and enhancing its interaction with VGLL4As discussed above and herein, Compound A down- regulates TEAD target genes in primary mesothelioma cells and inhibits growth of primary mesothelioma cells in a VGLL4-dependent manner. As also described herein, the anti-tumor activity of Compound A in combination with the EGFR inhibitor osimertinib is dependent on both VGLL4 and TEAD1 expression. [0029] As described herein, it has been found that: ^ Compound A selectively inhibits TEAD1; Page 6 of 49 BUSINESS31347208.1 396661-058WO (209307) ^ Compound A achieved equivalent efficacy to panTEAD inhibitors with improved therapeutic index in preclinical species; ^ Compound A shifts the equilibrium of TEAD1 towards a repressive transcriptional state, by disrupting its interaction with YAP1 and enhancing its interaction with VGLL4; ^ TEAD1 is the most highly expressed paralog in mesothelioma and EHE tumors, VGLL4 is highly expressed in these tumors as well; and ^ Compound A drives TEAD1 into a repressive complex that functionally antagonizes pro-tumorigenic transcriptional machinery. [0030] Accordingly, in some embodiments, the present disclosure provides a method of identifying or selecting a patient having an elevated VGLL4 level, comprising measuring the VGLL4 level in a tissue sample of the patient, and selecting a patient having an elevated VGLL4 level in the tissue sample. [0031] In some embodiments, provided herein is a method of treating a proliferative disorder in a patient having or identified as having an elevated VGLL4 level, for example, as determined using a method described herein, comprising administering to the patient a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof. [0032] In some embodiments, the present disclosure provides a method of treating a proliferative disorder in a patient, comprising selecting a patient having an elevated VGLL4 level, for example, using a method as described herein, and administering to the patient a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof. [0033] Accordingly, in some embodiments, the present disclosure provides a method of identifying or selecting a patient having an elevated TEAD1 level, comprising measuring the TEAD1 level in a tissue sample of the patient, and selecting a patient having an elevated TEAD1 level in the tissue sample. [0034] In some embodiments, provided herein is a method of treating a proliferative disorder in a patient having or identified as having an elevated TEAD1 level, for example, as determined using a method described herein, comprising administering to the patient a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof. [0035] In some embodiments, the present disclosure provides a method of treating a proliferative disorder in a patient, comprising selecting a patient having an elevated TEAD1 level, Page 7 of 49 BUSINESS31347208.1 396661-058WO (209307) for example, using a method as described herein, and administering to the patient a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof. [0036] Accordingly, in some embodiments, the present disclosure provides a method of identifying or selecting a patient having an elevated TEAD1 level and an elevated VGLL4 level, comprising measuring the TEAD1 level and the VGLL4 level in a tissue sample of the patient, and selecting a patient having an elevated TEAD1 level and an elevated VGLL4 level in the tissue sample. [0037] In some embodiments, provided herein is a method of treating a proliferative disorder in a patient having or identified as having an elevated TEAD1 level and an elevated VGLL4 level, for example, as determined using a method described herein, comprising administering to the patient a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof. [0038] In some embodiments, the present disclosure provides a method of treating a proliferative disorder in a patient, comprising selecting a patient having an elevated TEAD1 level and an elevated VGLL4 level, for example, using a method as described herein, and administering to the patient a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof. 2. Definitions [0039] As used herein, the term “Compound A” or “Compound A free base” refers to a TEAD inhibitor N-methyl-3-(1-methyl-1H-imidazol-4-yl)-4-((4-(trifluoromethyl)benzyl)amino), of formula: . In some embodiments, Compound A, or a pharmaceutically

In some embodiments, Compound A, or a pharmaceutically acceptable salt thereof, is in crystal form. [0040] As used herein, the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of Page 8 of 49 BUSINESS31347208.1 396661-058WO (209307) humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1–19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this disclosure include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2– hydroxy–ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2–naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3–phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p–toluenesulfonate, undecanoate, valerate salts, and the like. [0041] Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N⁺(C_1–4alkyl)₄ salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate. [0042] Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the disclosure. Unless otherwise stated, all tautomeric forms of the compounds of the disclosure are within the scope of the disclosure. Additionally, unless Page 9 of 49 BUSINESS31347208.1 396661-058WO (209307) otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures including the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a ¹³C- or ¹⁴C-enriched carbon are within the scope of this disclosure. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present disclosure. [0043] As used herein, the terms “treatment,” “treat,” and “treating” refer to preventing, reversing, alleviating, reducing the severity of, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, as described herein. In some embodiments, treatment can be administered after one or more symptoms have developed. In other embodiments, treatment can be administered in the absence of symptoms. For example, treatment can be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of genetic or other susceptibility factors). Treatment can also be continued after symptoms have resolved, for example to prevent or delay their recurrence. [0044] As used herein, the terms “patient” or “subject” refer to an animal, preferably a mammal, and most preferably a human. [0045] As used herein, a patient or subject “in need of prevention,” “in need of treatment,” or “in need thereof,” refers to one, who by the judgment of an appropriate medical practitioner (e.g., a doctor, a nurse, or a nurse practitioner in the case of humans; a veterinarian in the case of non- human mammals), would reasonably benefit from a given treatment or therapy. [0046] As used herein, the term “therapeutically effective amount” or “therapeutically effective dosage” of a drug or therapeutic agent, such as Compound A, is any amount of the drug that, when used alone or in combination with another therapeutic agent, protects a patient or subject against the onset of a disease, such as cancer, or promotes disease regression evidenced by a decrease in severity of disease symptoms, an increase in frequency and duration of disease symptom-free periods, or a prevention of impairment or disability due to the disease affliction. The ability of a therapeutic agent to promote disease regression can be evaluated using a variety of methods known to the skilled practitioner, such as in human subjects during clinical trials, in animal model systems predictive of efficacy in humans, or by assaying the activity of the agent in in vitro assays. In some embodiments, “a therapeutically effective amount of” refers to the amount of compound A, or a pharmaceutically acceptable salt thereof, which is effective to suppress cancer Page 10 of 49 BUSINESS31347208.1 396661-058WO (209307) cell growth in a biological sample or in a patient. In some embodiments, “a therapeutically effective amount of” refers to the amount of Compound A, or a pharmaceutically acceptable salt thereof, which measurably increases vestigial like 4 peptide (VGLL4) binding to TEAD1 in a cell. In some embodiments, “a therapeutically effective amount of” refers to the amount of Compound A, or a pharmaceutically acceptable salt thereof, which measurably increases the formation of a TEAD1/VGLL4 complex or a TEAD1/VGLL4/TEAD4 complex. [0047] As used herein, the terms “measurable increase” or “measurably increase” refers to a measurable increase of a substance (e.g., VGLL4, TEAD1, VGLL4 binding to TEAD1, TEAD1/VGLL4 complex, or TEAD1/VGLL4/TEAD4 complex) between a sample comprising Compound A, or a salt or a composition thereof, and an equivalent sample in the absence of Compound A, or a salt or composition thereof. [0048] As used herein, the terms "increases," “elevates,” or “enhances,” are used interchangeably and encompass any measurable increase in a biological function and/or biological activity and/or a concentration. For example, an increase can be by at least about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 100%, about 2-fold, about 3-fold, about 4- fold, about 5-fold, about 6-fold, about 7-fold, about 8-fold, about 9-fold, about 10-fold, about 20- fold, about 25-fold, about 50-fold, about 100-fold, or higher, relative to a control or baseline amount of a function, or activity, or concentration. [0049] As used herein, the terms “elevated level,” or “increased level,” of a substance (e.g., VGLL4, TEAD1, VGLL4 binding to TEAD1, TEAD1/VGLL4 complex, or TEAD1/VGLL4/TEAD4 complex) in a sample refers to an increase in the amount of the substance of about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 100%, about 2-fold, about 3-fold, about 4-fold, about 5-fold, about 6-fold, about 7-fold, about 8-fold, about 9-fold, about 10-fold, about 20-fold, about 25-fold, about 50-fold, about 100-fold, or higher, relative to the amount of the substance in a control sample or control samples, such as an individual or group of individuals who are not suffering from the disease or disorder (e.g., cancer) or an internal control, as determined by techniques known in the art. A subject can also be determined Page 11 of 49 BUSINESS31347208.1 396661-058WO (209307) to have an “elevated concentration” of a substance if the concentration of the substance is increased by one standard deviation, two standard deviations, three standard deviations, four standard deviations, five standard deviations, or more relative to the mean (average) or median amount of the substance in a control group of samples or a baseline group of samples or a retrospective analysis of patient samples. As practiced in the art, such control or baseline levels can be previously determined, or measured prior to the measurement in the sample, or can be obtained from a database of such control samples. In other words, the control and subject samples do not have to be tested simultaneously. Similarly, “reduced concentration,” “decreased concentrations,” “lowered levels,” or “reduced levels” refers to a decrease in concentration or a decrease in level by at least about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, or 100% in a sample relative to a control. [0050] As used herein, the terms “about” or “approximately” have the meaning of within 20% of a given value or range. In some embodiments, the term “about” refers to within 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% of a given value. 3. Description of Exemplary Methods and Uses [0051] In some aspects and embodiments, the present disclosure provides methods of identifying or selecting a patient having an elevated VGLL4 level for treatment with Compound A, the methods comprising measuring the VGLL4 level in a tissue sample of the patient, for example, using a method as described herein, and selecting a patient having an elevated VGLL4 level in the tissue sample. In some embodiments, the method further comprises administering Compound A, or a pharmaceutically acceptable salt thereof, to the patient having the elevated VGLL4 level. In some embodiments, a patient has a proliferative disorder. In some embodiments, a proliferative disorder is a cancer. In some embodiments, a cancer is selected from those as described herein. In some embodiments, a tissue sample is a cancer tissue sample. [0052] For use in the methods described herein, any screening assay for measuring the VGLL4 level normalizes the obtained VGLL4 level or concentration against the level or concentration of VGLL4 in the same tissue sample. Page 12 of 49 BUSINESS31347208.1 396661-058WO (209307) [0053] Accordingly, as used herein the terms “elevated VGLL4 level,” “increased VGLL4 level,” “increased VGLL4 level in a tissue sample,” and “elevated VGLL4 level in a tissue sample,” refer to a concentration or level of VGLL4 normalized to the concentration of VGLL4 in a tissue sample of a patient or subject, which is higher than the normal normalized concentration of VGLL4 in the tissue, or equal to or higher than a selected or prespecified or predefined normalized concentration or level of VGLL4 in the tissue. This higher value can be an increase in the amount of normalized VGLL4 of about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 100%, about 1.5 fold, about 2-fold, about 3-fold, about 4-fold, about 5-fold, about 6-fold, about 7-fold, about 8-fold, about 9-fold, about 10-fold, about 20-fold, about 25-fold, about 50-fold, about 100-fold, or higher, relative to the amount of normalized VGLL4 in a control sample or control samples, such as an individual or group of individuals who are not suffering from the disease or disorder (e.g., cancer), or a control sample databased based on retrospective patient sample analysis, or an internal control, as determined by techniques known in the art. A tissue sample from a subject can also be determined or deemed to have an “elevated concentration or level of VGLL4” if the normalized concentration or level of VGLL4 is increased by one standard deviation, two standard deviations, three standard deviations, four standard deviations, five standard deviations, or more, relative to the mean (average) or median amount of the substance in a control group of samples or a baseline group of samples. As practiced in the art, such control or baseline levels can be previously determined, or measured prior to the measurement in the sample, or can be obtained from a database of such control samples. [0054] Accordingly, in some embodiments of any of the aspects described herein, an elevated concentration or level of VGLL4 in a tissue sample refers to a normalized concentration or level of VGLL4 in a tissue sample about 20% higher relative to the amount of normalized VGLL4 in a control sample or control samples. In some embodiments of any of the aspects described herein, an elevated concentration or level of VGLL4 in a tissue sample refers to a normalized concentration or level of VGLL4 in a tissue sample about 40% higher relative to the amount of normalized VGLL4 in a control sample or control samples. In some embodiments of any of the aspects described herein, an elevated concentration or level of VGLL4 in a tissue sample refers to a normalized concentration or level of VGLL4 in a tissue sample about 60% higher relative to the Page 13 of 49 BUSINESS31347208.1 396661-058WO (209307) amount of normalized VGLL4 in a control sample or control samples. In some embodiments of any of the aspects described herein, an elevated concentration or level of VGLL4 in a tissue sample refers to a normalized concentration or level of VGLL4 in a tissue sample about 80% higher relative to the amount of normalized VGLL4 in a control sample or control samples. In some embodiments of any of the aspects described herein, an elevated concentration or level of VGLL4 in a tissue sample refers to a normalized concentration or level of VGLL4 in a tissue sample about 100% higher relative to the amount of normalized VGLL4 in a control sample or control samples. In some embodiments, an elevated concentration or level of VGLL4 in a tissue sample refers to a normalized concentration or level of VGLL4 in a tissue sample about 2-fold higher relative to the amount of normalized VGLL4 in a control sample or control samples. In some embodiments, an elevated concentration or level of VGLL4 in a tissue sample refers to a normalized concentration or level of VGLL4 in a tissue sample about 5-fold higher relative to the amount of normalized VGLL4 in a control sample or control samples. In some embodiments, an elevated concentration or level of VGLL4 in a tissue sample refers to a normalized concentration or level of VGLL4 in a tissue sample about 10-fold higher relative to the amount of normalized VGLL4 in a control sample or control samples. In some embodiments, an elevated concentration or level of VGLL4 in a tissue sample refers to a normalized concentration or level of VGLL4 in a tissue sample about 25-fold higher relative to the amount of normalized VGLL4 in a control sample or control samples. In some embodiments, an elevated concentration or level of VGLL4 in a tissue sample refers to a normalized concentration or level of VGLL4 in a tissue sample about 50-fold higher relative to the amount of normalized VGLL4 in a control sample or control samples. In some embodiments, an elevated concentration or level of VGLL4 in a tissue sample refers to a normalized concentration or level of VGLL4 in a tissue sample about 100-fold higher relative to the amount of normalized VGLL4 in a control sample or control samples. [0055] In some aspects and embodiments, a method of identifying or selecting a patient having an elevated tissue concentration or level of VGLL4 is for selecting a patient having a proliferative disorder, or a cancer. [0056] In some aspects and embodiments, the present disclosure provides methods of identifying or selecting a patient having an elevated TEAD1 level for treatment with Compound A, the methods comprising measuring the TEAD1 level in a tissue sample of the patient, for example, using a method as described herein, and selecting a patient having an elevated TEAD1 Page 14 of 49 BUSINESS31347208.1 396661-058WO (209307) level in the tissue sample. In some embodiments, the method further comprises administering Compound A, or a pharmaceutically acceptable salt thereof, to the patient having the elevated TEAD1 level. In some embodiments, a patient has a proliferative disorder. In some embodiments, a proliferative disorder is a cancer. In some embodiments, a cancer is selected from those as described herein. In some embodiments, a tissue sample is a cancer tissue sample. [0057] For use in the methods described herein, any screening assay for measuring the TEAD1 level normalizes the obtained TEAD1 level or concentration against the level or concentration of TEAD1 in the same tissue sample. [0058] Accordingly, as used herein the terms “elevated TEAD1 level,” “increased TEAD1 level,” “increased TEAD1 level in a tissue sample,” and “elevated TEAD1 level in a tissue sample,” refer to a concentration or level of TEAD1 normalized to the concentration of TEAD1 in a tissue sample of a patient or subject, which is higher than the normal normalized concentration of TEAD1 in the tissue, or equal to or higher than a selected or prespecified or predefined normalized concentration or level of TEAD1 in the tissue. This higher value can be an increase in the amount of normalized TEAD1 of about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 100%, about 1.5 fold, about 2-fold, about 3-fold, about 4-fold, about 5-fold, about 6-fold, about 7-fold, about 8-fold, about 9-fold, about 10-fold, about 20-fold, about 25-fold, about 50-fold, about 100-fold, or higher, relative to the amount of normalized TEAD1 in a control sample or control samples, such as an individual or group of individuals who are not suffering from the disease or disorder (e.g., cancer), or a control sample databased based on retrospective patient sample analysis, or an internal control, as determined by techniques known in the art. A tissue sample from a subject can also be determined or deemed to have an “elevated concentration or level of TEAD1” if the normalized concentration or level of TEAD1 is increased by one standard deviation, two standard deviations, three standard deviations, four standard deviations, five standard deviations, or more, relative to the mean (average) or median amount of the substance in a control group of samples or a baseline group of samples. As practiced in the art, such control or baseline levels can be previously determined, or measured prior to the measurement in the sample, or can be obtained from a database of such control samples. Page 15 of 49 BUSINESS31347208.1 396661-058WO (209307) [0059] Accordingly, in some embodiments of any of the aspects described herein, an elevated concentration or level of TEAD1 in a tissue sample refers to a normalized concentration or level of TEAD1 in a tissue sample about 20% higher relative to the amount of normalized TEAD1 in a control sample or control samples. In some embodiments of any of the aspects described herein, an elevated concentration or level of TEAD1 in a tissue sample refers to a normalized concentration or level of TEAD1 in a tissue sample about 40% higher relative to the amount of normalized TEAD1 in a control sample or control samples. In some embodiments of any of the aspects described herein, an elevated concentration or level of TEAD1 in a tissue sample refers to a normalized concentration or level of TEAD1 in a tissue sample about 60% higher relative to the amount of normalized TEAD1 in a control sample or control samples. In some embodiments of any of the aspects described herein, an elevated concentration or level of TEAD1 in a tissue sample refers to a normalized concentration or level of TEAD1 in a tissue sample about 80% higher relative to the amount of normalized TEAD1 in a control sample or control samples. In some embodiments of any of the aspects described herein, an elevated concentration or level of TEAD1 in a tissue sample refers to a normalized concentration or level of TEAD1 in a tissue sample about 100% higher relative to the amount of normalized TEAD1 in a control sample or control samples. In some embodiments, an elevated concentration or level of TEAD1 in a tissue sample refers to a normalized concentration or level of TEAD1 in a tissue sample about 2-fold higher relative to the amount of normalized TEAD1 in a control sample or control samples. In some embodiments, an elevated concentration or level of TEAD1 in a tissue sample refers to a normalized concentration or level of TEAD1 in a tissue sample about 5-fold higher relative to the amount of normalized TEAD1 in a control sample or control samples. In some embodiments, an elevated concentration or level of TEAD1 in a tissue sample refers to a normalized concentration or level of TEAD1 in a tissue sample about 10-fold higher relative to the amount of normalized TEAD1 in a control sample or control samples. In some embodiments, an elevated concentration or level of TEAD1 in a tissue sample refers to a normalized concentration or level of TEAD1 in a tissue sample about 25-fold higher relative to the amount of normalized TEAD1 in a control sample or control samples. In some embodiments, an elevated concentration or level of TEAD1 in a tissue sample refers to a normalized concentration or level of TEAD1 in a tissue sample about 50-fold higher relative to the amount of normalized TEAD1 in a control sample or control samples. In some embodiments, an elevated concentration or level of TEAD1 in a tissue sample refers to a normalized Page 16 of 49 BUSINESS31347208.1 396661-058WO (209307) concentration or level of TEAD1 in a tissue sample about 100-fold higher relative to the amount of normalized TEAD1 in a control sample or control samples. [0060] In some aspects and embodiments, a method of identifying or selecting a patient having an elevated tissue concentration or level of TEAD1 is for selecting a patient having a proliferative disorder, or a cancer. [0061] In some aspects and embodiments, the present disclosure provides methods of identifying or selecting a patient having an elevated TEAD1 level and an elevated VGLL4 level for treatment with Compound A, the methods comprising measuring the TEAD1 level and the VGLL4 level in a tissue sample of the patient, for example, using a method as described herein, and selecting a patient having an elevated TEAD1 level and an elevated VGLL4 level in the tissue sample. In some embodiments, the method further comprises administering Compound A, or a pharmaceutically acceptable salt thereof, to the patient having an elevated TEAD1 level and an elevated VGLL4 level. In some embodiments, a patient has a proliferative disorder. In some embodiments, a proliferative disorder is a cancer. In some embodiments, a cancer is selected from those as described herein. In some embodiments, a tissue sample is a cancer tissue sample. [0062] In some aspects and embodiments, a method of identifying or selecting a patient having an elevated tissue concentration or level of TEAD1 and VGLL4 is for selecting a patient having a proliferative disorder, or a cancer. [0063] In some embodiments, a cancer is selected from those as described herein. In some embodiments, a cancer is selected from mesothelioma, meningioma, cholangiocarcinoma, thymoma, non-small cell lung cancer (NSCLC; both squamous and adenocarcinoma, including mucoepidermoid NSCLC), hepatocellular carcinoma (HCC), and epithelioid hemangioendothelioma (EHE). [0064] In some aspects and embodiments, the present disclosure provides a method of treating a proliferative disorder in a patient having or identified as having an elevated VGLL4 level, for example, as determined using a method described herein, comprising administering to the patient a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a method for treating a proliferative disorder in a patient, comprising selecting a patient having an elevated VGLL4 level, and administering to the patient a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof. In some embodiments, an elevated VGLL4 level is as described herein. Page 17 of 49 BUSINESS31347208.1 396661-058WO (209307) [0065] In some aspects and embodiments, the present disclosure provides a method of treating a proliferative disorder in a patient having or identified as having an elevated TEAD1 level, for example, as determined using a method described herein, comprising administering to the patient a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a method for treating a proliferative disorder in a patient, comprising selecting a patient having an elevated TEAD1 level, and administering to the patient a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof. In some embodiments, an elevated TEAD1 level is as described herein. [0066] In some aspects and embodiments, the present disclosure provides a method of treating a proliferative disorder in a patient having or identified as having an elevated TEAD1 level and an elevated VGLL4 level, for example, as determined using a method described herein, comprising administering to the patient a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a method for treating a proliferative disorder in a patient, comprising selecting a patient having an elevated TEAD1 level and an elevated VGLL4 level, and administering to the patient a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof. In some embodiments, an elevated TEAD1 level is as described herein. In some embodiments, an elevated VGLL4 level is as described herein. [0067] In some embodiments, a proliferative disorder is a cancer. In some embodiments, a cancer is malignant mesothelioma. In some embodiments, a cancer is advanced unresectable malignant mesothelioma. In some embodiments, a cancer is sarcomatoid malignant mesothelioma. In some embodiments, a cancer is epitheliod malignant mesothelioma. In some embodiments, a cancer is meningioma. In some embodiments, a cancer is sporadic menongioma. In some embodiments, a cancer is recurrent or unresectable meningioma. In some embodiments, a cancer is cholangiocarcinoma. In some embodiments, a cancer is non-small cell lung cancer (NSCLC; both squamous and adenocarcinoma, including mucoepidermoid NSCLC). In some embodiments, a cancer is head and neck squamous cell carcinoma (HNSCC). In some embodiments, a cancer is esophageal carcinoma. In some embodiments, a cancer is ovarian carcinoma. In some embodiments, a cancer is endometrial carcinoma. In some embodiments, a cancer is cervical carcinoma. In some embodiments, a cancer is hepatocellular carcinoma. In some embodiments, a cancer is mesothelioma. In some embodiments, a cancer is a neurofibromatosis type 2. In some Page 18 of 49 BUSINESS31347208.1 396661-058WO (209307) embodiments, a cancer is a brain tumor. In some embodiments, a cancer is epithelioid hemangioendothelioma (EHE). In some embodiments, a cancer is thymoma. In some embodiments, a cancer is a schwannoma. In some embodiments, a cancer is malignant pleural mesothelioma (MPM). In some embodiments, a cancer is angiosarcoma. In some embodiments, a cancer is liposarcoma. In some embodiments, a cancer is synovial sarcoma. In some embodiments, a cancer is myxoid liposarcoma. In some embodiments, a cancer is soft tissue sarcoma. In some embodiments, a cancer is a solid tumor. In some embodiments, a cancer is a locally advanced or metastatic solid tumor. [0068] In some embodiments of a method provided herein, the method comprises administering to the patient about 25 – 1200 mg of Compound A, or a pharmaceutically acceptable salt thereof, daily. [0069] In some embodiments, a therapeutically effective amount of the drug, such as Compound A, promotes cancer regression to the point of eliminating the cancer. The term "promote(s) cancer regression" means that administering an effective amount of the drug, alone or in combination with another therapeutic agent, results in a reduction in tumor growth or size, necrosis of the tumor, a decrease in severity of at least one disease symptom, an increase in frequency and duration of disease symptom-free periods, or a prevention of impairment or disability due to the disease affliction. In addition, the terms "effective" and "effectiveness" with regard to a treatment includes both pharmacological effectiveness and physiological safety. Pharmacological effectiveness refers to the ability of the drug to promote cancer regression in the patient. Physiological safety refers to the level of toxicity, or other adverse physiological effects at the cellular, organ and/or organism level (adverse effects) resulting from administration of the drug. [0070] As used herein, the terms “therapeutic benefit” or "benefit from therapy" refers to an improvement in one or more of overall survival, progression-free survival, partial response, complete response, and overall response rate and can also include a reduction in cancer or tumor growth or size, a decrease in severity of disease symptoms, an increase in frequency and duration of disease symptom-free periods, or a prevention of impairment or disability due to the disease affliction. [0071] In some embodiments, a method of the present disclosure comprises administering once daily to a patient about 25 – 1200 mg of Compound A, or a pharmaceutically acceptable salt Page 19 of 49 BUSINESS31347208.1 396661-058WO (209307) thereof. In some embodiments, a method of the present disclosure comprises administering once daily to a patient about 25 mg of Compound A, or a pharmaceutically acceptable salt thereof. In some embodiments, a method of the present disclosure comprises administering once daily to a patient about 50 mg of Compound A, or a pharmaceutically acceptable salt thereof. In some embodiments, a method of the present disclosure comprises administering once daily to a patient about 75 mg of Compound A, or a pharmaceutically acceptable salt thereof. In some embodiments, a method of the present disclosure comprises administering once daily to a patient about 100 mg of Compound A, or a pharmaceutically acceptable salt thereof. In some embodiments, a method of the present disclosure comprises administering once daily to a patient about 125 mg of Compound A, or a pharmaceutically acceptable salt thereof. In some embodiments, a method of the present disclosure comprises administering once daily to a patient about 150 mg of Compound A, or a pharmaceutically acceptable salt thereof. In some embodiments, a method of the present disclosure comprises administering once daily to a patient about 200 mg of Compound A, or a pharmaceutically acceptable salt thereof. In some embodiments, a method of the present disclosure comprises administering once daily to a patient about 250 mg of Compound A, or a pharmaceutically acceptable salt thereof. In some embodiments, a method of the present disclosure comprises administering once daily to a patient about 300 mg of Compound A, or a pharmaceutically acceptable salt thereof. In some embodiments, a method of the present disclosure comprises administering once daily to a patient about 350 mg of Compound A, or a pharmaceutically acceptable salt thereof. In some embodiments, a method of the present disclosure comprises administering once daily to a patient about 400 mg of Compound A, or a pharmaceutically acceptable salt thereof. In some embodiments, a method of the present disclosure comprises administering once daily to a patient about 450 mg of Compound A, or a pharmaceutically acceptable salt thereof. In some embodiments, a method of the present disclosure comprises administering once daily to a patient about 500 mg of Compound A, or a pharmaceutically acceptable salt thereof. In some embodiments, a method of the present disclosure comprises administering once daily to a patient about 550 mg of Compound A, or a pharmaceutically acceptable salt thereof. In some embodiments, a method of the present disclosure comprises administering once daily to a patient about 600 mg of Compound A, or a pharmaceutically acceptable salt thereof. In some embodiments, a method of the present disclosure comprises administering once daily to a patient about 650 mg of Compound A, or a Page 20 of 49 BUSINESS31347208.1 396661-058WO (209307) pharmaceutically acceptable salt thereof. In some embodiments, a method of the present disclosure comprises administering once daily to a patient about 700 mg of Compound A, or a pharmaceutically acceptable salt thereof. In some embodiments, a method of the present disclosure comprises administering once daily to a patient about 750 mg of Compound A, or a pharmaceutically acceptable salt thereof. In some embodiments, a method of the present disclosure comprises administering once daily to a patient about 800 mg of Compound A, or a pharmaceutically acceptable salt thereof. In some embodiments, a method of the present disclosure comprises administering once daily to a patient about 850 mg of Compound A, or a pharmaceutically acceptable salt thereof. In some embodiments, a method of the present disclosure comprises administering once daily to a patient about 900 mg of Compound A, or a pharmaceutically acceptable salt thereof. In some embodiments, a method of the present disclosure comprises administering once daily to a patient about 950 mg of Compound A, or a pharmaceutically acceptable salt thereof. In some embodiments, a method of the present disclosure comprises administering once daily to a patient about 1000 mg of Compound A, or a pharmaceutically acceptable salt thereof. In some embodiments, a method of the present disclosure comprises administering once daily to a patient about 1100 mg of Compound A, or a pharmaceutically acceptable salt thereof. In some embodiments, a method of the present disclosure comprises administering once daily to a patient about 1200 mg of Compound A, or a pharmaceutically acceptable salt thereof. [0072] In some embodiments, a method of the present disclosure comprises administering twice daily to a patient about 25 – 1200 mg of compound A, or a pharmaceutically acceptable salt thereof. In some embodiments, a method of the present disclosure comprises administering twice daily to a patient about 25 mg of Compound A, or a pharmaceutically acceptable salt thereof. In some embodiments, a method of the present disclosure comprises administering twice daily to a patient about 50 mg of compound A, or a pharmaceutically acceptable salt thereof. In some embodiments, a method of the present disclosure comprises administering twice daily to a patient about 75 mg of Compound A, or a pharmaceutically acceptable salt thereof. In some embodiments, a method of the present disclosure comprises administering twice daily to a patient about 100 mg of Compound A, or a pharmaceutically acceptable salt thereof. In some embodiments, a method of the present disclosure comprises administering twice daily to a patient about 125 mg of Compound A, or a pharmaceutically acceptable salt thereof. In some embodiments, a method of Page 21 of 49 BUSINESS31347208.1 396661-058WO (209307) the present disclosure comprises administering twice daily to a patient about 150 mg of Compound A, or a pharmaceutically acceptable salt thereof. In some embodiments, a method of the present disclosure comprises administering twice daily to a patient about 200 mg of compound A, or a pharmaceutically acceptable salt thereof. In some embodiments, a method of the present disclosure comprises administering twice daily to a patient about 250 mg of Compound A, or a pharmaceutically acceptable salt thereof. In some embodiments, a method of the present disclosure comprises administering twice daily to a patient about 300 mg of Compound A, or a pharmaceutically acceptable salt thereof. In some embodiments, a method of the present disclosure comprises administering twice daily to a patient about 350 mg of Compound A, or a pharmaceutically acceptable salt thereof. In some embodiments, a method of the present disclosure comprises administering twice daily to a patient about 400 mg of compound A, or a pharmaceutically acceptable salt thereof. In some embodiments, a method of the present disclosure comprises administering twice daily to a patient about 450 mg of Compound A, or a pharmaceutically acceptable salt thereof. In some embodiments, a method of the present disclosure comprises administering twice daily to a patient about 500 mg of Compound A, or a pharmaceutically acceptable salt thereof. In some embodiments, a method of the present disclosure comprises administering twice daily to a patient about 550 mg of Compound A, or a pharmaceutically acceptable salt thereof. In some embodiments, a method of the present disclosure comprises administering twice daily to a patient about 600 mg of Compound A, or a pharmaceutically acceptable salt thereof. [0073] In some embodiments, the Compound A, or a pharmaceutically acceptable salt thereof, is administered on a continuous dosing schedule. In some embodiments, Compound A, or a pharmaceutically acceptable salt thereof, is administered on an intermittent dosing schedule. In some embodiments, Compound A, or a pharmaceutically acceptable salt thereof, is administered every day for the entire course of treatment. In some embodiments, Compound A, or a pharmaceutically acceptable salt thereof, is administered every day for two weeks followed by one week where Compound A, or a pharmaceutically acceptable salt thereof, is not administered. In some embodiments, Compound A is administered every day for two weeks followed by two weeks where Compound A, or a pharmaceutically acceptable salt thereof, is not administered. Page 22 of 49 BUSINESS31347208.1 396661-058WO (209307) [0074] In some embodiments, the present disclosure provides a use of Compound A, or a pharmaceutically acceptable salt thereof, for the treatment of solid tumors and/or cancers, such as those as described herein. 4. Methods and Uses for Treating Cancer The Hippo Signaling Network [0075] The Hippo signaling network (also known as the Salvador/Warts/Hippo (SWH) pathway) is a master regulator of cell proliferation, death, and differentiation. In some embodiments, the main function of the Hippo signaling pathway is to regulate negatively the transcriptional co-activators Yes-associated protein (YAP) and its paralogue, the transcriptional co-activator with PDZ-binding motif (TAZ; also known as WWTR1). The Hippo kinase cascade phosphorylates and inhibits YAP/TAZ by promoting its cytoplasmic retention and degradation, thereby inhibiting the growth promoting function regulated under the YAP/TAZ control. In an un- phosphorylated/de-phosphorylated state, YAP, also known as YAP1 or YAP65, together with TAZ, are transported into the nucleus where they interact with TEAD family of transcription factors to upregulate genes that promote proliferation and migration, and inhibit apoptosis. In some instances, unregulated upregulation of these genes involved in proliferation, migration, and anti- apoptosis leads to development of cancer. In some instances, overexpression of YAP/TAZ is associated with cancer. [0076] Additional core members of the Hippo signaling pathway comprise the serine/threonine kinases MST1/2 (homologues of Hippo/Hpo in Drosophila), Lats1/2 (homologues of Warts/Wts), and their adaptor proteins Sav1 (homologue of Salvador/Sav) and Mob (MOBKL1A and MOBKL1B; homologues of Mats), respectively. In general, MST1/2 kinase complexes with the scaffold protein Sav1, which in turn phosphorylates and activates Lats1/2 kinase. Lats1/2 is also activated by the scaffold protein Mob. The activated Lats1/2 then phosphorylates and inactivates YAP or its paralog TAZ. The phosphorylation of YAP/TAZ leads to their nuclear export, retention within the cytoplasm, and degradation by the ubiquitin proteasome system. [0077] In some embodiments, the present disclosure provides a use of a compound, or a pharmaceutical salt or composition thereof, for treating one or more disorders, diseases, and/or conditions wherein the disorder, disease, or condition includes, but is not limited to, a cellular proliferative disorder. Page 23 of 49 BUSINESS31347208.1 396661-058WO (209307) [0078] Detailed conditions for assaying Compound A are known in the art and described herein. See, for example, WO 2020243423 and WO 2020243415, the contents of each of which are incorporated herein by reference in their entireties. [0079] As used herein, the terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, as described herein. In some embodiments, treatment can be administered after one or more symptoms have developed. In other embodiments, treatment can be administered in the absence of symptoms. For example, treatment can be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of genetic or other susceptibility factors). Treatment can also be continued after symptoms have resolved, for example, to prevent or delay their recurrence. [0080] The provided Compound A is TEAD1 paralog selective inhibitor and is therefore useful for treating one or more disorders associated with activity of TEAD and activation of the Hippo pathway. [0081] As used herein, the term “a therapeutically effective amount of” refers to the amount of Compound A or a pharmaceutically acceptable salt thereof that provides a therapeutic benefit in the treatment of a condition, or delays or minimizes one or more symptoms associated with the condition in a biological sample or in a patient. In some embodiments, “a therapeutically effective amount of” refers to the amount of Compound A or a pharmaceutically acceptable salt thereof that measurably decreases the binding or signaling activity of TEAD1 with YAP1/TAZ and/or increases the binding or stability of TEAD1 with VGLL4. The term “therapeutically effective amount” can encompass, in some embodiments, an amount that improves overall therapy, reduces or avoids symptoms, signs, or causes of the condition, and/or enhances the therapeutic efficacy of another therapeutic agent. In certain embodiments, a therapeutically effective amount is an amount sufficient for treating a proliferative disease. [0082] In some aspects and embodiments, provided herein are methods of treating, reducing the severity of, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof of a disease or disorder characterized by or associated with elevated and/or increased VGLL4 and/or TEAD1 comprising the step of administering to a patient in need thereof a therapeutically effective compound of the present disclosure, or pharmaceutically acceptable composition thereof. Page 24 of 49 BUSINESS31347208.1 396661-058WO (209307) [0083] In some aspects and embodiments, the present disclosure provides a method for treating one or more disorders, diseases, and/or conditions wherein the disorder, disease, or condition includes, but is not limited to, a cellular proliferative disorder, comprising administering to a patient in need thereof, a Compound A as described herein, or a pharmaceutical salt or composition thereof. In some embodiments, a cellular proliferative disorder is cancer. In some embodiments, the cancer is characterized by increased VGLL4 and/or TEAD1 (expression and/or increased VGLL4 and/or TEAD1 activity. [0084] As used herein, the terms "increased," “elevated,” or “enhanced,” are used interchangeably and encompass any measurable increase in a biological function and/or biological activity and/or a concentration. For example, an increase can be by at least about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 100%, about 2-fold, about 3-fold, about 4- fold, about 5-fold, about 6-fold, about 7-fold, about 8-fold, about 9-fold, about 10-fold, about 20- fold, about 25-fold, about 50-fold, about 100-fold, or higher, relative to a control or baseline amount of a function, or activity, or concentration. [0085] As used herein, the terms “increased expression” and/or “increased activity” of a substance, such as VGLL4 and/or TEAD1, in a sample or cancer or patient, refers to an increase in the amount of the substance, such as VGLL4 and/or TEAD1, of about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 100%, about 2-fold, about 3-fold, about 4-fold, about 5-fold, about 6-fold, about 7-fold, about 8-fold, about 9-fold, about 10-fold, about 20-fold, about 25-fold, about 50-fold, about 100-fold, or higher, relative to the amount of the substance, such as VGLL4 and/or TEAD1, in a control sample or control samples, such as an individual or group of individuals who are not suffering from the disease or disorder (e.g., cancer) or an internal control, as determined by techniques known in the art. A subject can also be determined to have an “increased expression” or “increased activity” of VGLL4 and/or TEAD1 if the expression and/or activity of VGLL4 and/or TEAD1 is increased by one standard deviation, two standard deviations, three standard deviations, four standard deviations, five standard deviations, or more, relative to the mean (average) or median amount of VGLL4 and/or TEAD1 Page 25 of 49 BUSINESS31347208.1 396661-058WO (209307) in a control group of samples or a baseline group of samples or a retrospective analysis of patient samples. As practiced in the art, such control or baseline expression levels can be previously determined, or measured prior to the measurement in the sample or cancer or subject, or can be obtained from a database of such control samples. [0086] As used herein, a “proliferative disease” refers to a disease that occurs due to abnormal growth or extension by the multiplication of cells (Walker, Cambridge Dictionary of Biology, Cambridge University Press: Cambridge, UK, 1990). A proliferative disease can be associated with: 1) the pathological proliferation of normally quiescent cells; 2) the pathological migration of cells from their normal location (e.g., metastasis of neoplastic cells); 3) the pathological expression of proteolytic enzymes, such as the matrix metalloproteinases (e.g., collagenases, gelatinases, and elastases); or 4) the pathological angiogenesis as in proliferative retinopathy and tumor metastasis. Exemplary proliferative diseases include cancers (i.e., “malignant neoplasms”), benign neoplasms, angiogenesis, inflammatory diseases, and autoimmune diseases. Cancer [0087] The cancer or proliferative disorder or tumor to be treated using the compounds and methods and uses described herein include, but are not limited to, a hematological cancer, a lymphoma, a myeloma, a leukemia, a neurological cancer, skin cancer, breast cancer, a prostate cancer, a colorectal cancer, lung cancer, head and neck cancer, a gastrointestinal cancer, a liver cancer, a pancreatic cancer, a genitourinary cancer, a bone cancer, renal cancer, and a vascular cancer. [0088] In some embodiments of the methods and uses described herein, the cancer is characterized or associated with a genetic alteration in one or more Hippo pathway genes. As used herein, the term “genetic alteration in one or more Hippo pathway genes” refers to that certain percentage of cells in a sample, such as a tumor sample, having a detectable amount of genetic alteration in one or more Hippo pathway genes. As used herein, a genetic alteration in a gene, such as a Hippo pathway gene, can refer, for example, to a loss-of-function mutation in the gene (including, for example, frameshifts, nonsense mutations and splicing mutations), a change in gene copy number (including, for example, copy gain, amplification, copy loss, or deletion), or a fusion of the gene with another gene, such as, for example, a TAZ-CAMTA1 fusion or YAP1-TFE3 fusion. In some embodiments, a genetic alteration in Hippo pathway genes refers to that about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, Page 26 of 49 BUSINESS31347208.1 396661-058WO (209307) about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, or 100%of cells, such as tumor cells, in a sample have at least about three copies of genetically altered Hippo pathway genes, at least about four copies of genetically altered Hippo pathway genes, at least about five copies of genetically altered Hippo pathway genes, at least about six copies of genetically altered Hippo pathway genes, at least about seven copies of genetically altered Hippo pathway genes, at least about eight copies of genetically altered Hippo pathway genes, at least about nine copies of genetically altered Hippo pathway genes, at least about ten copies of genetically altered Hippo pathway genes, at least about eleven copies of genetically altered Hippo pathway genes, at least about twelve copies of genetically altered Hippo pathway genes, at least about nine copies of genetically altered Hippo pathway genes, at least about ten copies of genetically altered Hippo pathway genes, at least about eleven copies of genetically altered Hippo pathway genes, at least about twelve copies of genetically altered Hippo pathway genes, at least about thirteen copies of genetically altered Hippo pathway genes, at least about fourteen copies of genetically altered Hippo pathway genes, at least about fifteen copies of genetically altered Hippo pathway genes, at least about twenty copies of genetically altered Hippo pathway genes, or more. In some embodiments, genetic alteration in Hippo pathway genes refers to that about 10% tumor cells in a sample have at least about 15 copies of genetically altered Hippo pathway genes. In some embodiments, genetic alteration in Hippo pathway genes refers to that about 40% tumor cells in a sample have at least about 4 copies of genetically altered Hippo pathway genes. In some embodiments, genetic alteration in Hippo pathway genes refers to that about 10% tumor cells in a sample have at least about four copies of genetically altered Hippo pathway genes. [0089] In some embodiments, a Hippo pathway gene is NF2. In some embodiments, the genetic alteration in the one or more Hippo pathway genesis NF2 deficiency. In some embodiments, NF2 deficiency refers to NF2 loss of function mutations. In some embodiments, NF2 deficiency refers to NF2 copy losses or deletions. In some embodiments, NF2 deficiency refers to absent or very low NF2 mRNA expression. In some embodiments, a Hippo pathway gene is YAP1. In some embodiments, the genetic alteration in the one or more Hippo pathway genes is YAP1 amplification. In some embodiments, the genetic alteration in the one or more Hippo pathway genes is a YAP1 fusion, such as a YAP1-TFE3 fusion. In some embodiments, a Hippo pathway gene is TAZ. In some embodiments, the genetic alteration in the one or more Hippo Page 27 of 49 BUSINESS31347208.1 396661-058WO (209307) pathway genes is TAZ amplification. In some embodiments, the genetic alteration in the one or more Hippo pathway genes is a TAZ fusion, such as a TAZ-CAMTA1 fusion. In some embodiments, a Hippo pathway gene is LATS 1/2. In some embodiments, the genetic alteration in the one or more Hippo pathway genes is LATS 1/2 copy number loss or deletion. In some embodiments, a Hippo pathway gene is MST1/2. In some embodiments, a Hippo pathway gene is BAP1. [0090] In some embodiments, the cancer is selected from a mesothelioma, meningioma, cholangiocarcinoma, non-small cell lung cancer (NSCLC), head and neck squamous cell carcinoma (HNSCC), esophageal carcinoma, ovarian carcinoma, endometrial carcinoma, cervical carcinoma, hepatocellular carcinoma, brain tumor, epithelioid hemangioendothelioma (EHE), thymoma, schwannoma, angiosarcoma, liposarcoma, synovial sarcoma, and soft tissue sarcoma. [0091] In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is a locally advanced or metastatic solid tumor. [0092] In some embodiments, the cancer is mesothelioma. In some embodiments, the cancer is malignant mesothelioma. In some embodiments, the cancer is advanced unresectable malignant mesothelioma. In some embodiments, the cancer is malignant pleural mesothelioma (MPM). In some embodiments, the cancer is sarcomatoid malignant mesothelioma. In some embodiments, the cancer is epithelioid malignant mesothelioma. [0093] In some embodiments, the cancer is meningioma. In some embodiments, the cancer is sporadic meningioma. In some embodiments, the cancer is recurrent or unresectable meningioma. [0094] In some embodiments, the cancer is cholangiocarcinoma. In some embodiments, the cancer is non-small cell lung cancer (NSCLC). In some embodiments, the cancer is squamous NSCLC, adenocarcinoma NSCLC, and mucoepidermoid NSCLC. [0095] In some embodiments, the cancer is head and neck squamous cell carcinoma (HNSCC). [0096] In some embodiments, the cancer is esophageal carcinoma. [0097] In some embodiments, the cancer is ovarian carcinoma. [0098] In some embodiments, the cancer is endometrial carcinoma. [0099] In some embodiments, the cancer is cervical carcinoma. [00100] In some embodiments, the cancer is hepatocellular carcinoma. [00101] In some embodiments, the cancer is a neurofibromatosis type 2 (NF2)-deficient cancer. [00102] In some embodiments, the cancer is a brain tumor. Page 28 of 49 BUSINESS31347208.1 396661-058WO (209307) [00103] In some embodiments, the cancer is epithelioid hemangioendothelioma (EHE). [00104] In some embodiments, the cancer is thymoma. [00105] In some embodiments, the cancer is a schwannoma. [00106] In some embodiments, the cancer is angiosarcoma. [00107] In some embodiments, the cancer is liposarcoma. [00108] In some embodiments, the cancer is synovial sarcoma. [00109] In some embodiments, the cancer is myxoid liposarcoma. [00110] In some embodiments, the cancer is soft tissue sarcoma. [00111] In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is a locally advanced or metastatic solid tumor. [00112] In some embodiments, the cancer is mesothelioma. In some embodiments, the cancer malignant pleural mesothelioma (MPM). [00113] In some embodiments, the cancer is an NF2-deficient MPM. NF2-deficient tumors are defined, in some embodiments, as any NF2 loss-of-function mutations or copy number loss. [00114] In some embodiments, the cancer is EHE. In some embodiments, the EHE has TAZ- CAMTA1 or YAP1-TFE3 gene fusions. [00115] In some embodiments, the cancer is a solid tumors with one or more YAP1/TAZ gene fusions. [00116] In some embodiments, the cancer is an EGFR mutant cancer. In some embodiments, the EGFR mutant cancer harbors the EGFR L858R mutation. In some embodiments, the EGFR mutant cancer harbors the EGFR T790M mutation. In some embodiments, the EGFR mutant cancer harbors the EGFR C797S mutation. In some embodiments, the EGFR mutant cancer comprises an EGFR 19 deletion. In some embodiments, the EGFR mutant cancer is EGFRm NSCLC. In some embodiments, the EGFR mutant cancer isTKI-resistant, EGFRm NSCLC. [00117] In some embodiments, the cancer is a K-Ras mutant cancer. In some embodiments, the K-Ras mutant cancer is an activated mutant K-Ras cancer. In some embodiments, the K-Ras mutant cancer is a cancer having a mutant or variant K-Ras G12. In some embodiments, the mutant or variant K-Ras G12 is K-Ras G12D, K-Ras G12V, K-Ras G12C, K-Ras G12R, K-Ras G12A, or any combination thereof. In some embodiments, the mutant or variant K-Ras G12 is K-Ras G12D. In some embodiments, the mutant or variant K-Ras G12 is K-Ras G12V. In some embodiments, the mutant or variant K-Ras G12 is K-Ras G12C. In some embodiments, the mutant or variant K- Page 29 of 49 BUSINESS31347208.1 396661-058WO (209307) Ras G12 is K-Ras G12R. In some embodiments, the mutant or variant K-Ras G12 is K-Ras G12A. In some embodiments, the K-Ras mutant cancer is a cancer having a mutant or variant K-Ras G13. In some embodiments, the mutant or variant K-Ras G13 is K-Ras G13D, K-Ras G13C, or any combination thereof. In some embodiments, the K-Ras mutant cancer is a cancer having a mutant or variant K-Ras Q61. In some embodiments, the mutant or variant K-Ras Q61 is K-Ras Q61H, K-Ras Q61R, or any combination thereof. In some embodiments, the K-Ras mutant cancer is a cancer having a mutant or variant K-Ras A146. In some embodiments, the mutant or variant K- Ras A146 is K-Ras A146T. In some embodiments, the K-Ras mutant cancer is a cancer having a mutant or variant K-Ras G12D, K-Ras G12V, K-Ras G12C, K-Ras G12R, K-Ras G12A, K-Ras G13D, K-Ras G13C, K-Ras Q61H, K-Ras Q61R, K-Ras A146T, or any combination thereof. [00118] In some embodiments, cancer includes, without limitation, leukemias (e.g., acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, acute myeloblastic leukemia, acute promyelocytic leukemia, acute myelomonocytic leukemia, acute monocytic leukemia, acute erythroleukemia, chronic leukemia, chronic myelocytic leukemia, chronic lymphocytic leukemia), polycythemia vera, lymphoma (e.g., Hodgkin’s disease or non-Hodgkin’s disease), Waldenstrom's macroglobulinemia, multiple myeloma, heavy chain disease, and solid tumors such as sarcomas and carcinomas (e.g., fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing’s tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilm's tumor, cervical cancer, uterine cancer, testicular cancer, lung carcinoma, small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, glioblastoma multiforme (GBM, also known as glioblastoma), medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, schwannoma, neurofibrosarcoma, meningioma, melanoma, neuroblastoma, and retinoblastoma). [00119] In some embodiments, the cancer is glioma, astrocytoma, glioblastoma multiforme (GBM, also known as glioblastoma), medulloblastoma, craniopharyngioma, ependymoma, Page 30 of 49 BUSINESS31347208.1 396661-058WO (209307) pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, schwannoma, neurofibrosarcoma, meningioma, melanoma, neuroblastoma, or retinoblastoma. [00120] In some embodiments, the cancer is acoustic neuroma, astrocytoma (e.g., Grade I – Pilocytic Astrocytoma, Grade II – Low-grade Astrocytoma, Grade III – Anaplastic Astrocytoma, or Grade IV – Glioblastoma (GBM)), chordoma, CNS lymphoma, craniopharyngioma, brain stem glioma, ependymoma, mixed glioma, optic nerve glioma, subependymoma, medulloblastoma, meningioma, metastatic brain tumor, oligodendroglioma, pituitary tumors, primitive neuroectodermal (PNET) tumor, or schwannoma. In some embodiments, the cancer is a type found more commonly in children than adults, such as brain stem glioma, craniopharyngioma, ependymoma, juvenile pilocytic astrocytoma (JPA), medulloblastoma, optic nerve glioma, pineal tumor, primitive neuroectodermal tumors (PNET), or rhabdoid tumor. In some embodiments, the patient is an adult human. In some embodiments, the patient is a child or pediatric patient. [00121] Cancer includes, in another embodiment, without limitation, mesothelioma, hepatobilliary (hepatic and billiary duct), bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, ovarian cancer, colon cancer, rectal cancer, cancer of the anal region, stomach cancer, gastrointestinal (gastric, colorectal, and duodenal), uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin’s Disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, testicular cancer, chronic or acute leukemia, chronic myeloid leukemia, lymphocytic lymphomas, cancer of the bladder, cancer of the kidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis, non-Hodgkins’s lymphoma, spinal axis tumors, brain stem glioma, pituitary adenoma, adrenocortical cancer, gall bladder cancer, multiple myeloma, cholangiocarcinoma, fibrosarcoma, neuroblastoma, retinoblastoma, or a combination of one or more of the foregoing cancers. [00122] In some embodiments, the cancer is selected from hepatocellular carcinoma, ovarian cancer, ovarian epithelial cancer, or fallopian tube cancer; papillary serous cystadenocarcinoma or uterine papillary serous carcinoma (UPSC); prostate cancer; testicular cancer; gallbladder cancer; hepatocholangiocarcinoma; soft tissue and bone synovial sarcoma; rhabdomyosarcoma; osteosarcoma; chondrosarcoma; Ewing sarcoma; anaplastic thyroid cancer; adrenocortical Page 31 of 49 BUSINESS31347208.1 396661-058WO (209307) adenoma; pancreatic cancer; pancreatic ductal carcinoma or pancreatic adenocarcinoma; gastrointestinal/stomach (GIST) cancer; lymphoma; squamous cell carcinoma of the head and neck (SCCHN); salivary gland cancer; glioma, or brain cancer; neurofibromatosis-1 associated malignant peripheral nerve sheath tumors (MPNST); Waldenstrom’s macroglobulinemia; or medulloblastoma. [00123] In some embodiments, the cancer is selected from hepatocellular carcinoma (HCC), hepatoblastoma, colon cancer, rectal cancer, ovarian cancer, ovarian epithelial cancer, fallopian tube cancer, papillary serous cystadenocarcinoma, uterine papillary serous carcinoma (UPSC), hepatocholangiocarcinoma, soft tissue and bone synovial sarcoma, rhabdomyosarcoma, osteosarcoma, anaplastic thyroid cancer, adrenocortical adenoma, pancreatic cancer, pancreatic ductal carcinoma, pancreatic adenocarcinoma, glioma, neurofibromatosis-1 associated malignant peripheral nerve sheath tumors (MPNST), Waldenstrom’s macroglobulinemia, or medulloblastoma. [00124] In some embodiments, a cancer is a solid tumor, such as a sarcoma, carcinoma, or lymphoma. Solid tumors generally comprise an abnormal mass of tissue that typically does not include cysts or liquid areas. In some embodiments, the cancer is selected from renal cell carcinoma, or kidney cancer; hepatocellular carcinoma (HCC) or hepatoblastoma, or liver cancer; melanoma; breast cancer; colorectal carcinoma, or colorectal cancer; colon cancer; rectal cancer; anal cancer; lung cancer, such as non-small cell lung cancer (NSCLC) or small cell lung cancer (SCLC); ovarian cancer, ovarian epithelial cancer, ovarian carcinoma, or fallopian tube cancer; papillary serous cystadenocarcinoma or uterine papillary serous carcinoma (UPSC); prostate cancer; testicular cancer; gallbladder cancer; hepatocholangiocarcinoma; soft tissue and bone synovial sarcoma; rhabdomyosarcoma; osteosarcoma; chondrosarcoma; Ewing sarcoma; anaplastic thyroid cancer; adrenocortical carcinoma; pancreatic cancer; pancreatic ductal carcinoma or pancreatic adenocarcinoma; gastrointestinal/stomach (GIST) cancer; lymphoma; squamous cell carcinoma of the head and neck (SCCHN); salivary gland cancer; glioma, or brain cancer; neurofibromatosis-1 associated malignant peripheral nerve sheath tumors (MPNST); Waldenstrom’s macroglobulinemia; or medulloblastoma. [00125] In some embodiments, the cancer is selected from renal cell carcinoma, hepatocellular carcinoma (HCC), hepatoblastoma, colorectal carcinoma, colorectal cancer, colon cancer, rectal cancer, anal cancer, ovarian cancer, ovarian epithelial cancer, ovarian carcinoma, fallopian tube Page 32 of 49 BUSINESS31347208.1 396661-058WO (209307) cancer, papillary serous cystadenocarcinoma, uterine papillary serous carcinoma (UPSC), hepatocholangiocarcinoma, soft tissue and bone synovial sarcoma, rhabdomyosarcoma, osteosarcoma, chondrosarcoma, anaplastic thyroid cancer, adrenocortical carcinoma, pancreatic cancer, pancreatic ductal carcinoma, pancreatic adenocarcinoma, glioma, brain cancer, neurofibromatosis-1 associated malignant peripheral nerve sheath tumors (MPNST), Waldenstrom’s macroglobulinemia, or medulloblastoma. [00126] In some embodiments, the cancer is selected from hepatocellular carcinoma (HCC), hepatoblastoma, colon cancer, rectal cancer, ovarian cancer, ovarian epithelial cancer, ovarian carcinoma, fallopian tube cancer, papillary serous cystadenocarcinoma, uterine papillary serous carcinoma (UPSC), hepatocholangiocarcinoma, soft tissue and bone synovial sarcoma, rhabdomyosarcoma, osteosarcoma, anaplastic thyroid cancer, adrenocortical carcinoma, pancreatic cancer, pancreatic ductal carcinoma, pancreatic adenocarcinoma, glioma, neurofibromatosis-1 associated malignant peripheral nerve sheath tumors (MPNST), Waldenstrom’s macroglobulinemia, or medulloblastoma. [00127] In some embodiments, the cancer is hepatocellular carcinoma (HCC). In some embodiments, the cancer is hepatoblastoma. In some embodiments, the cancer is colon cancer. In some embodiments, the cancer is rectal cancer. In some embodiments, the cancer is ovarian cancer, or ovarian carcinoma. In some embodiments, the cancer is ovarian epithelial cancer. In some embodiments, the cancer is fallopian tube cancer. In some embodiments, the cancer is papillary serous cystadenocarcinoma. In some embodiments, the cancer is uterine papillary serous carcinoma (UPSC). In some embodiments, the cancer is hepatocholangiocarcinoma. In some embodiments, the cancer is soft tissue and bone synovial sarcoma. In some embodiments, the cancer is rhabdomyosarcoma. In some embodiments, the cancer is osteosarcoma. In some embodiments, the cancer is anaplastic thyroid cancer. In some embodiments, the cancer is adrenocortical carcinoma. In some embodiments, the cancer is pancreatic cancer, or pancreatic ductal carcinoma. In some embodiments, the cancer is pancreatic adenocarcinoma. In some embodiments, the cancer is glioma. In some embodiments, the cancer is malignant peripheral nerve sheath tumors (MPNST). In some embodiments, the cancer is neurofibromatosis-1 associated MPNST. In some embodiments, the cancer is Waldenstrom’s macroglobulinemia. In some embodiments, the cancer is medulloblastoma. Page 33 of 49 BUSINESS31347208.1 396661-058WO (209307) [00128] In some embodiments, a cancer is a viral-associated cancer, including human immunodeficiency virus (HIV) associated solid tumors, human papilloma virus (HPV)-16 positive incurable solid tumors, and adult T-cell leukemia, which is caused by human T-cell leukemia virus type I (HTLV-I) and is a highly aggressive form of CD4+ T-cell leukemia characterized by clonal integration of HTLV-I in leukemic cells (See https://clinicaltrials.gov/ct2/show/study/ NCT02631746); as well as virus-associated tumors in gastric cancer, nasopharyngeal carcinoma, cervical cancer, vaginal cancer, vulvar cancer, squamous cell carcinoma of the head and neck, and Merkel cell carcinoma. (See https://clinicaltrials.gov/ct2/show/study/NCT02488759; see also https://clinicaltrials.gov/ct2/show/study/NCT0240886; https://clinicaltrials.gov/ct2/show/ NCT02426892). [00129] In some embodiments, the present disclosure provides a method for treating cancer in a patient comprising orally administering to the patient a formulation as described herein. In some embodiments, the present disclosure provides a method for treating cancer in a patient comprising orally administering to the patient a unit dosage form as described herein. In some embodiments, the present disclosure provides a method for treating cancer in a patient comprising orally administering to the patient a tablet as described herein. [00130] In some embodiments, the methods or uses described herein inhibit or reduce or arrest the growth or spread of a cancer or tumor. In some embodiments, the tumor or cancer is treated by arresting, reducing, or inhibiting further growth of the tumor. In some embodiments, the cancer or tumor is treated using the methods or uses described herein by reducing the size (e.g., volume or mass) of the cancer or tumor by at least 5%, at least 10%, at least 25%, at least 50%, at least 75%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% relative to the size of the cancer or tumor prior to treatment. In some embodiments, cancers or tumors are treated using the methods or uses described herein by reducing the quantity of the cancers or tumors in the patient by at least 5%, at least 10%, at least 25%, at least 50%, at least 75%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% relative to the quantity of tumors prior to treatment. [00131] In some embodiments, the tumor is treated by arresting further growth of the tumor. In some embodiments, the tumor is treated by reducing the size (e.g., volume or mass) of the tumor by at least 5%, 10%, 25%, 50%, 75%, 90% or 99% relative to the size of the tumor prior to treatment. In some embodiments, tumors are treated by reducing the quantity of the tumors in the Page 34 of 49 BUSINESS31347208.1 396661-058WO (209307) patient by at least 5%, 10%, 25%, 50%, 75%, 90% or 99% relative to the quantity of tumors prior to treatment. [00132] In some embodiments, a patient treated using the methods or uses described herein exhibits progression-free survival of at least about one month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about one year, at least about eighteen months, at least about two years, at least about three years, at least about four years, or at least about five years after administration of Compound A, or a pharmaceutically acceptable salt thereof. In some embodiments, a patient treated using the methods or uses described herein exhibits an overall survival of at least about one month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about one year, at least about 14 months, at least about 16 months, at least about 18 months, at least about 20 months, at least about 22 months, at least about two years, at least about three years, at least about four years, or at least about five years after administration of Compound A, or a pharmaceutically acceptable salt thereof. In some embodiments, a patient treated using the methods or uses described herein exhibits an objective response rate (ORR) of at least about 15%, at least about 20%, at least about 25%, at least about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%. [00133] In some embodiments, a patient treated using the methods or uses described herein exhibits progression-free survival of at least about one month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about one year, at least about eighteen months, at least about two years, at least about three years, at least about four years, or at least about five years after administration of a metabolite of Compound A, or a pharmaceutically acceptable salt thereof, or a prodrug thereof. In some embodiments, a patient treated using the methods or uses described herein exhibits an overall survival of at least about one month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, Page 35 of 49 BUSINESS31347208.1 396661-058WO (209307) at least about one year, at least about 14 months, at least about 16 months, at least about 18 months, at least about 20 months, at least about 22 months, at least about two years, at least about three years, at least about four years, or at least about five years after administration of a metabolite of Compound A, or a pharmaceutically acceptable salt thereof, or a prodrug thereof. [00134] In some embodiments, a patient treated using the methods or uses described herein exhibits an objective response rate (ORR) of at least about 15%, at least about 20%, at least about 25%, at least about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%. a. Co-Administration with One or More Other Therapeutic Agent(s) [00135] Depending upon the particular condition, or disease, to be treated, additional therapeutic agents that are normally administered to treat that condition, can also be used in the methods described herein. As used herein, additional therapeutic agents that are normally administered to treat a particular disease, or condition, are known as "appropriate for the disease, or condition, being treated." [00136] In some embodiments, the present disclosure provides a method of treating a disclosed disease or condition comprising administering to a patient in need thereof an effective amount of Compound A disclosed herein or a pharmaceutically acceptable salt thereof and co-administering simultaneously or sequentially an effective amount of one or more additional therapeutic agents, such as those described herein. In some embodiments, the method includes co-administering one additional therapeutic agent. In some embodiments, the method includes co-administering two additional therapeutic agents. In some embodiments, the combination of Compound A and the additional therapeutic agent or agents acts synergistically. [00137] Compound A can be administered alone or in combination with one or more other therapeutic compounds, possible combination therapy taking the form of fixed combinations or the administration of Compound A and one or more other therapeutic compounds being staggered or given independently of one another, or the combined administration of fixed combinations and one or more other therapeutic compounds. [00138] One or more other therapeutic agent(s) can be administered separately from Compound A, as part of a multiple dosage regimen. Alternatively, one or more other therapeutic agent(s) may be part of a single dosage form, mixed together with Compound A in a single composition. If Page 36 of 49 BUSINESS31347208.1 396661-058WO (209307) administered as a multiple dosage regime, one or more other therapeutic agent(s) and Compound A can be administered simultaneously, sequentially or within a period of time from one another, for example within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 hours from one another. In some embodiments, one or more other therapeutic agent(s) and a Compound A are administered as a multiple dosage regimen within greater than 24 hours apart. [00139] As used herein, the term "combination," "combined," and related terms refers to the simultaneous or sequential administration of therapeutic agents in accordance with this disclosure. For example, Compound A can be administered with one or more other therapeutic agent(s) simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form. Accordingly, the present disclosure provides a single unit dosage form comprising a Compound A, one or more other therapeutic agent(s), and a pharmaceutically acceptable carrier, adjuvant, or vehicle. [00140] The amount of Compound A and one or more other therapeutic agent(s) (in those compositions which comprise an additional therapeutic agent as described above) that can be combined with the carrier materials to produce a single dosage form varies depending upon the host treated and the particular mode of administration. Preferably, Compound A should be formulated so that a dosage of between 0.01 - 100 mg/kg body weight/day of Compound A can be administered. [00141] In those compositions which comprise one or more other therapeutic agent(s), the one or more other therapeutic agent(s) and Compound A can act synergistically. Therefore, the amount of the one or more other therapeutic agent(s) in such compositions may be less than that required in a monotherapy utilizing only that therapeutic agent. In such compositions a dosage of between 0.01 - 1,000 g/kg body weight/day of the one or more other therapeutic agent(s) can be administered. [00142] The amount of one or more other therapeutic agent(s) present in the compositions of this disclosure may be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent. Preferably the amount of one or more other therapeutic agent(s) in the presently disclosed compositions ranges from about 50% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent. In some embodiments, one or more other therapeutic agent(s) is administered at a dosage of about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, Page 37 of 49 BUSINESS31347208.1 396661-058WO (209307) about 80%, about 85%, about 90%, or about 95% of the amount normally administered for that agent. As used herein, the phrase "normally administered" means the amount an FDA approved therapeutic agent is approved for dosing per the FDA label insert. [00143] Compound A, or pharmaceutical compositions thereof, can also be incorporated into compositions for coating an implantable medical device, such as prostheses, artificial valves, vascular grafts, stents and catheters. Vascular stents, for example, have been used to overcome restenosis (re-narrowing of the vessel wall after injury). However, patients using stents or other implantable devices risk clot formation or platelet activation. These unwanted effects may be prevented or mitigated by pre-coating the device with a pharmaceutically acceptable composition comprising a kinase inhibitor. Implantable devices coated with Compound A are another embodiment of the present disclosure. b. Exemplary Other Therapeutic Agents [00144] In some embodiments, a one or more other therapeutic agent is an EGFR inhibitor. As used herein, an “EGFR inhibitor” refers to any inhibitor or blocker or antagonist that binds to and/or inhibits epidermal growth factor receptor (EGFR). In some embodiments, an EGFR inhibitor is selected from those as described in Ayati et al., “A review on progression of epidermal growth factor receptor (EGFR) inhibitors as an efficient approach in cancer targeted therapy,” Bioorganic Chemistry 2020, 99: 103811, the contents of which are incorporated herein by reference in their entirety. In some embodiments, an EGFR inhibitor is selected from cetuximab, necitumumab, panitumumab, zalutumumab, nimotuzumab, and matuzumab. In some embodiments, an EGFR inhibitor is cetuximab. In some embodiments, an EGFR inhibitor is necitumumab. In some embodiments, an EGFR inhibitor is panitumumab. In some embodiments, an EGFR inhibitor is zalutumumab. In some embodiments, an EGFR inhibitor is nimotuzumab. In some embodiments, an EGFR inhibitor is matuzumab. [00145] In some embodiments, an EGFR inhibitor is selected from osimertinib, gefitinib, erlotinib, lapatinib, neratinib, vandetanib, afatinib, brigatinib, dacomitinib, and icotinib. In some embodiments, an EGFR inhibitor is osimertinib. In some embodiments, an EGFR inhibitor is gefitinib. In some embodiments, an EGFR inhibitor is erlotinib. In some embodiments, an EGFR inhibitor is lapatinib. In some embodiments, an EGFR inhibitor is neratinib. In some embodiments, an EGFR inhibitor is vandetanib. In some embodiments, an EGFR inhibitor is afatinib. In some Page 38 of 49 BUSINESS31347208.1 396661-058WO (209307) embodiments, an EGFR inhibitor is brigatinib. In some embodiments, an EGFR inhibitor is dacomitinib. In some embodiments, an EGFR inhibitor is icotinib. [00146] In some embodiments, an EGFR inhibitor is a “1st generation EGFR tyrosine kinase inhibitor” (“1st generation TKI”). A 1st generation TKI refers to reversible EGFR inhibitors, such as gefitinib and erlotinib, which are effective in first-line treatment of, for example, NSCLC harboring EGFR activating mutations, such as deletions in exon 19 and exon 21 L858R mutation. [00147] In some embodiments, an EGFR inhibitor is a “2nd generation EGFR tyrosine kinase inhibitor” (“2nd generation TKI”). A 2nd generation TKI refers to covalent irreversible EGFR inhibitors, such as afatinib and dacomitib, which are effective in first-line treatment of NSCLC harboring EGFR activating mutations, such as deletions in exon 19 and exon 21 L858R mutation. [00148] In some embodiments, an EGFR inhibitor is a “3rd generation EGFR tyrosine kinase inhibitor” (“3rd generation TKI”). A 3rd generation TKI refers to covalent irreversible EGFR inhibitors, such as osimertinib and lazertinib, which are selective to the EGFR activating mutations, such as deletions in exon 19 and exon 21 L858R, alone or in combination with T790M mutation, and have lower inhibitory activity against wild-type EGFR. [00149] In some embodiments, the one or more other therapeutic agent is a KRAS inhibitor, such as a KRAS G12C inhibitor. As used herein, a “KRAS G12C inhibitor” refers to any inhibitor or blocker or antagonist that binds to and/or inhibits signaling through KRAS. In certain embodiments, a KRAS G12C inhibitor is selected from adagrasib (KRAZATI®, Mirati Therapeutics), sotorasib (LUMAKRAS® and LUMYKRAS®, Amgen), or a pharmaceutically acceptable salt and/or solvate of any of the foregoing. Other examples of KRAS G12C inhibtiors for use in the methods and uses described herein include, but are not limited to, JDQ-443 (Novartis AG), D-1553 (Inventisbio Shanghai), GF-105 (GenFleet Therapeutics), GH-35 (Suzhou GenHouse Bio Co.), JAB-21822 (Jacobio Pharmaceuticals), JMKX-001899 (Shanghi Jiyu Pharmaceuticals), TAS-119 (Taiho Pharmaceuticals), XNW-14010 (Suzhou Sinovent Pharmaceuticals), YL-15293 (Shanghai Yingli Pharmaceuticals), ZG-19018 (Suzhou Zelgen Biopharma), BEBT-607 (Guangzhou Bibet Pharmaceuticals), BI-1701963 (Forma Therapeutics Holdings), BI-1823911 (Boehringer Ingelheim Gmbh), BPI-421286 (Betta Pharmaceuticals), D3S-001 (D3 Bio), ERAS-3490 (Regents of the University of California), GEC-255 (GenEros BioPhrma LTD), and JS116 (Shanghai Junshi Biosceinces). Other examples of KRAS G12C inhibitors in the methods and uses described herein include, but are not limited to, those described Page 39 of 49 BUSINESS31347208.1 396661-058WO (209307) in international patent publications WO 2021/120890 the contents of each of which are herein incorporated by reference in their entireties. [00150] In some embodiments, the one or more other therapeutic agent is a pan-RAF inhibitor. As used herein, a “Pan-RAF inhibitor” refers to any inhibitor or blocker or antagonist that binds to all known members of the serine/threonine protein kinase Raf family including A-Raf, B-Raf, and C-Raf protein kinases, with potential antineoplastic activity. In certain embodiments, a Pan- RAF inhibitor is selected from tovorafenib (TAK580, Day One Biopharmaceuticals), TAK-632 (Takeda Pharmaceuticals), lifirafenib (BGB-283, BeiGene), exarafenib (Kinnate Biopharma), naporafenib (LXH-254, Erasca), or a pharmaceutically acceptable salt and/or solvate of any of the foregoing. In certain embodiments, a Pan-RAF inhibitor is selected from tovorafenib TAK-632, lifirafenib, exarafenib, or a pharmaceutically acceptable salt and/or solvate of any of the foregoing. Other examples of Pan-RAF inhibitors useful with the compositions, methods, and uses described herein include, but are not limited to, those described in international patent publications WO2015/075483, WO2015/075483, and WO2014/151616 the contents of each of which are herein incorporated by reference in their entireties. EXEMPLIFICATION [00151] Compound A can be prepared as described herein and by methods known to one of ordinary skill in the art, for example, as described in US 2020/0407327, the contents of which are incorporated herein by reference in their entireties. Example 1. [00152] A BODIPY-palmitate Fluorescence Polarization (FP) competition assay was used as one assay to compare binding of Compound A or a pan-TEAD inhibitor to recombinant TEAD1- 4 YAP1-binding domain, as shown in FIG. 2A and summarized in FIG. 2D. Fluorescence polarization measures changes in light polarization due to compound competition with fluorescent- labeled BODIPY palmitate. [00153] A cell-based NanoBRET assay was used to compare binding of Compound A or a pan- TEAD inhibitor to full length TEAD1-4, as shown in FIG. 2B and summarized in FIG. 2D. Following transfection of TEADx-HiBiT and LgBiT DNA constructs, 293T cells were seeded into 384 well plates. The next day, a tracer (BODIPY-linked palmitoylation inhibitor) was added along Page 40 of 49 BUSINESS31347208.1 396661-058WO (209307) with a dose response of Compound A or a pan-TEAD inhibitor. Six hours later, plates were processed with the NANOBRET NANO-GLO reagent according to the manufacturer's instructions and read using an ENVISION plate reader. Concentration response curves demonstrating binding of Compound A or a pan-TEAD inhibitor to full length TEAD1-4 expressed in 293T cells are shown. [00154] A click chemistry assay was used to show blocking of alkyl-palmitoyl-CoA by Compound A or a pan-TEAD inhibitor binding to recombinant TEAD1-4 YAP1-binding domain (YBD), as shown in FIG.2C and summarized in FIG.2D. Purified recombinant TEAD-YBD was incubated with compounds for 30 minutes, then alkyne-palmitoyl-CoA for an additional 30 minutes. The reaction was quenched with 1% SDS then followed by click chemistry reaction with biotin-azide using a kit from ThermoFisher following the manufacturer’s instructions. Palmitoylated TEAD and total TEAD protein was detected by immunoblotting using anti-TEAD antibodies and streptavidin. [00155] The NF2-deficient mesothelioma tumor NCI-H226 was grown as a xenograft in mice to determine anti-tumor activity, as shown in FIG. 3A. Mice were randomized into 4 groups: vehicle; panTEADi 3mpk; panTEADi 1mpk, and Compound A at 75mpk. Changes in tumor size were measured until 30 days of treatment and are represented in mm³, as shown in FIG. 3A Histopathology and morbidity safety findings were determined. Average peak urinary protein-to- creatinine ratios relative to average exposures (AUC0-24h, ng-h/ml) in monkeys treated with Compound A or a pan-TEAD inhibitor for 28 days was determined, as shown in FIG.3C. [00156] PC9 and H226 cells were infected with a puromycin TEAD-luciferase vector. Cells were then treated with puromycin to select those expressing the TEAD-luciferase reporter system. Luciferase signal corresponding to TEAD reporter activity was determined in PC9 (upper panels) and NCI-H226 (lower panels) cells transfected with siRNAs targeting TEAD1 (siTEAD1) and VGLL4 (siVGLL4) relative to a negative control siRNA (siMock) (FIG. 4A). Endogenous expression of TEAD target genes CTGF and CYR61 in PC9 (upper panels) and NCI-H226 (lower panels) cells transfected with siRNAs targeting TEAD1 (siTEAD1) relative to a negative control siRNA (siMock) were determined by reverse-transcriptase quantitative PCR analysis on RNA isolated from the cells five (5) days after transfection with siRNAs (FIG.4B). [00157] TEAD1-YAP1 co-immunoprecipitation was performed in FLAG-TEAD1 knock-in MSTO-211H cells treated with 25 nM and 1mM Compound A, a pan-TEAD inhibitor, or DMSO Page 41 of 49 BUSINESS31347208.1 396661-058WO (209307) control. Using CRISPR technology, an N-terminal FLAG epitope tag was inserted onto TEAD1 in MSTO-211H cells. Homozygous knock-in clones were selected and confirmed by PCR. As shown in FIG.5A, MSTO-211H cells harboring a FLAG tag at the endogenous TEAD1 locus were treated with 25 nM or 1 µM of Compound A or a pan-TEAD inhibitor for 24 hours. The next day, cell lysates were generated, equilibrated, and subjected to anti-FLAG immunoprecipitation with M2-conjugated beads overnight. Following several rounds of washes, immunoprecipitated material was eluted and with whole cell extracts subjected to SDS-PAGE and western blot analysis with the indicated anti-FLAG and anti-YAP antibodies. As shown in FIG. 5B, 293T cells were transiently transfected with TEAD1-Flag, HA-VGLL4, and myc-YAP5SA constructs. Forty-eight (48) hours later, transfected cells were treated with DMSO or 1 µM of Compound A or a panTEAD inhibitor for 24 hours, followed by cell lysis and overnight anti-Flag immunoprecipitation with M2-conjugated beads. The next day beads were washed, and eluted material and whole cell extracts were subjected to SDS-PAGE and western blot with the indicated antibodies. As shown in FIG. 5C, 293T cells were transiently transfected with TEAD1-Flag, myc-YAP5SA, and HA- VGLL4 (WT or MUT H219A/F220A/H246A/F247A) - constructs. Forty-eight (48) hours later, transfected cells were treated with DMSO or 1 µM of Compound A for 24 hours, followed by cell lysis and overnight immunoprecipitation with M2-conjugated beads. The next day, beads were washed, and eluted material and whole cell extracts were subjected to SDS-PAGE and western blot with the indicated antibodies. [00158] RNA sequencing data from a primary mesothelioma cell line upon treatment with two concentrations of Compound A was analyzed using DESeq2 and changes in expression of TEAD target genes were represented in a Heatmap as Z-transformed expression levels normalized relative to DMSO, as shown in FIG.6A. As shown in FIG.6B and FIG.6C, change in cell numbers of a primary mesothelioma cell line transiently expressing siRNAs targeting TEAD1 (siTEAD1) or a negative control siRNA (siMOCK) upon treatment with Compound A (1uM) or DMSO using time lapse microscopy for cell number quantification (an INCUCYTE cell count system). Stable polyclonal Mero 14 cell lines expressing doxycycline-inducible VGLL4-WT and VGLL4-mutant proteins were established with lentiviral infection. The VGLL4-mutant construct has four (4) point mutations (H212A, F213A, H240A, F241A), which disrupt binding of the TDU1 and TDU2 domains to TEAD. Both constructs contain an HA epitope tag. Cells were treated with different concentrations of doxycycline for 24 hours, lysed, and immunoblotted with anti-HA antibody to Page 42 of 49 BUSINESS31347208.1 396661-058WO (209307) test for induced VGLL4 expression. Cells were plated in 96-well plates and treated with indicated doses of doxycycline and Compound A simultaneously. Western blot analyses was performed to assess doxycycline-induced expression of HA-tagged wild-type VGLL4 (WT) or HA-tagged VGLL4 mutated in the TDU-TEAD interaction domains (MUTANT) in Mero14 mesothelioma cells, as shown in FIG.6D. The effect of a range of concentrations of Compound A on cell growth in Mero14 cells expressing an empty vector control, VGLL4WT, or VGLL4MUTANT, induced with different 10 ng/ml or 25 ng/ml of doxycycline was determined using a CELL TITER GLOW (CTG) proliferation assay five (5) days after treatment initiation, as shown in FIG.6E. [00159] Western blot analysis was performed to measure knockdown of TEAD1 or TEAD4 in EGFR mutant PC9 cells with TEAD1 (sgTEAD1) or TEAD4 (sgTEAD4) knocked out using CRISPR relative to non-selective control (sgControl). As shown in FIG. 7A, to generate control and TEAD1 knockout lines, Cas9 protein-sgRNA (sgControl or sgTEAD1) complexes were introduced into PC9 cells with the NEON transfection system. Several days later, knockout efficiency was checked via SDS-PAGE and western blot analysis with the indicated antibodies. As shown in FIG.7B, to assess apoptosis induction, control or knockout (TEAD1 or VGLL4) cell lines were seeded in 96 well plates and the following day treated with 1 µM osimtertinib +/- 1 uM Compound A. A caspase-activated fluorescent probe was added and apoptosis induction over time was monitored using an INCUCYTE Live-cell analysis machine according to the manufacturer’s instructions. As shown in FIG.7C, apoptosis induction over time was measured in PC9 sgControl, sgTEAD1 or sgTEAD4 cells treated with DMSO, osimertinib (1 µM), or a combination of osimertinib and Compound A (1 µM) was measured using a caspase-activate fluorescent probe (Incucyte). Apoptosis induction over time in PC9 sgControl, or sgVGLL4 cells treated with DMSO, osimertinib (1 µM) or combination of osimertinib and Compound A (1 µM) was measured using a caspase-activated fluorescent probe (INCUCYTE). [00160] As shown in FIG.8A – FIG.8E, TEAD paralog expression in mesothelioma versus all other tumor types from The Cancer Genome Atlas (TCGA) database was performed (expression in TPM percentile among same-length or longer transcripts). TEAD paralog expression was determined in primary mesothelioma cell lines (n=19), mesothelioma cell lines in DepMap, and all other cell lines in DepMap (TPM). TEAD paralog expression was determined in EHE tumor samples (n=6) and all tumors in TCGA (TPM). VGLL4 expression by tumor type was analyzed in TCGA (TPM). VGLL4 expression in EHE tumor samples (n=6), in EHE samples from Page 43 of 49 BUSINESS31347208.1 396661-058WO (209307) GSE168493 (Seavey et al., Genes Development 2021) or in all tumors in TCGA (TPM) was determined. [00161] While we have described a number of embodiments of this disclosure, it is apparent that our basic examples may be altered to provide other embodiments that utilize the compounds and methods of this disclosure. Therefore, it will be appreciated that the scope of this disclosure is to be defined by the application and claims rather than by the specific embodiments that have been represented by way of example. Page 44 of 49 BUSINESS31347208.1 396661-058WO (209307)

Claims

CLAIMS 1. A method of treating a proliferative disorder in a patient, comprising: selecting a patient having an elevated VGLL4 level and/or an elevated TEAD1 level; and administering to the patient a therapeutically effective amount of Compound A: a pharmaceutically acceptable salt thereof.

2. The method of claim 1, wherein the proliferative disorder is a cancer.

3. The method of claim 2, wherein the cancer is mesothelioma, meningioma, non-small cell lung cancer, head and neck squamous cell carcinoma, esophageal carcinoma, ovarian carcinoma, endometrial carcinoma, cervical carcinoma, hepatocellular carcinoma, brain tumor, epithelioid hemangioendothelioma (EHE), thymoma, schwannoma, angiosarcoma, liposarcoma, synovial sarcoma, myxoid liposarcoma, or soft tissue sarcoma.

4. The method of any one of claims 1-3, further comprising measuring the VGLL4 level and/or TEAD1 level in a tissue sample of a patient.

5. The method of any one of claims 1-4, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered once or twice daily at a dosage of about 25 – 1200 mg per administration.

6. A method for identifying or selecting a patient having a proliferative disorder for treatment with Compound A, or a pharmaceutically acceptable salt thereof, comprising: measuring the VGLL4 level and/or TEAD1 level in a tissue sample of a patient; and selecting a patient having an elevated VGLL4 level and/or TEAD1 level in the tissue sample. Page 45 of 49 BUSINESS31347208.1 396661-058WO (209307)

7. The method of claim 6, wherein the proliferative disorder is a cancer.

8. The method of claim 7, wherein the cancer is mesothelioma, menongioma, non-small cell lung cancer, head and neck squamous cell carcinoma, esophageal carcinoma, ovarian carcinoma, endometrial carcinoma, cervical carcinoma, hepatocellular carcinoma, brain tumor, epithelioid hemangioendothelioma (EHE), thymoma, schwannoma, angiosarcoma, liposarcoma, synovial sarcoma, myxoid liposarcoma, or soft tissue sarcoma.

9. The method of any one of claims 6-8, further comprising administering to the patient having the elevated VGLL4 level and/or TEAD1 level a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof.

10. The method of any one of claims 6-9, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered once or twice daily at a dosage of about 25 – 1200 mg per administration.

11. A method for identifying or selecting a patient having a proliferative disorder for treatment with Compound A, or a pharmaceutically acceptable salt thereof, comprising: selecting a patient having an elevated VGLL4 level and/or TEAD1 level; and administering to the patient a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof.

12. The method of claim 11, wherein the proliferative disorder is a cancer.

13. The method of claim 12, wherein the cancer is mesothelioma, meningioma, non-small cell lung cancer, head and neck squamous cell carcinoma, esophageal carcinoma, ovarian carcinoma, endometrial carcinoma, cervical carcinoma, hepatocellular carcinoma, brain tumor, epithelioid hemangioendothelioma (EHE), thymoma, schwannoma, angiosarcoma, liposarcoma, synovial sarcoma, myxoid liposarcoma, or soft tissue sarcoma. Page 46 of 49 BUSINESS31347208.1 396661-058WO (209307)

14. The method of any one of claims 11-13, further comprising measuring the VGLL4 level and/or TEAD1 level in a tissue sample of a patient.

15. The method of any one of claims 11-14, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered once or twice daily at a dosage of about 25 – 1200 mg per administration.

16. A method of treating a patient having a proliferative disorder and identified as having an elevated VGLL4 level and/or TEAD1 level, comprising administering to the patient a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof.

17. The method of claim 16, wherein the proliferative disorder is a cancer.

18. The method of claim 17, wherein the cancer is mesothelioma, meningioma, non-small cell lung cancer, head and neck squamous cell carcinoma, esophageal carcinoma, ovarian carcinoma, endometrial carcinoma, cervical carcinoma, hepatocellular carcinoma, brain tumor, epithelioid hemangioendothelioma (EHE), thymoma, schwannoma, angiosarcoma, liposarcoma, synovial sarcoma, myxoid liposarcoma, or soft tissue sarcoma.

19. The method of any one of claims 16-18, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered once or twice daily at a dosage of about 25 – 1200 mg per administration.

20. A method of treating a proliferative disorder in a patient having an elevated VGLL4 level and/or TEAD1 level, comprising administering to the patient a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof.

21. The method of claim 20, wherein the proliferative disorder is a cancer.

22. The method of claim 21, wherein the cancer is mesothelioma, meningioma, non-small cell lung cancer, head and neck squamous cell carcinoma, esophageal carcinoma, ovarian carcinoma, Page 47 of 49 BUSINESS31347208.1 396661-058WO (209307) endometrial carcinoma, cervical carcinoma, hepatocellular carcinoma, brain tumor, epithelioid hemangioendothelioma (EHE), thymoma, schwannoma, angiosarcoma, liposarcoma, synovial sarcoma, myxoid liposarcoma, or soft tissue sarcoma.

23. The method of any one of claims 20-22, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered once or twice daily at a dosage of about 25 – 1200 mg per administration. Page 48 of 49 BUSINESS31347208.1 396661-058WO (209307)