TEAD inhibitor dosing regimens

Abstract

The present invention relates to a TEAD inhibitor, or a pharma- ceutically acceptable salt thereof, for use in the treatment of cancer, wherein the TEAD inhibitor, or a pharma- ceutically acceptable salt thereof, is administered on each of the first three days of a seven-day treatment cycle, and wherein the treatment comprises at least two treatment cycles.

Description

[Technical field]

[0001] The present invention relates to a TEAD inhibitor, or a pharma- ceutically acceptable salt thereof, for use in the treatment of cancer, and to a particular dosing regimen, for example, where the TEAD inhibitor is administered on each of the first three days of a seven-day treatment cycle, and the treatment comprises at least two treatment cycles. [Background technology]

[0002] Normal tissue growth, as well as tissue repair and remodeling, require specific control and balancing of transcriptional activity. Transcriptional output is coordinated through several key signaling modules, one of which is the Hippo pathway. Genetic studies in Drosophila and mammals have defined a conserved core signaling cassette composed of Mst1 / 2 and Lats1 / 2 kinases that inhibit the transcriptional coactivators YAP and TAZ (official gene name: WWTR1).

[0003] An activated Hippo pathway phosphorylates and sequesters / degrades YAP and TAZ in the cytoplasm. When the Hippo pathway is inactivated, YAP and TAZ are translocated to the nucleus and bind to transcription factors, namely members of the TEAD family (TEAD1-4). The YAP / TAZ-TEAD complex then promotes the transcription of downstream genes involved in cell proliferation, death, and differentiation. Although YAP and TAZ may also interact with several other factors, it is generally accepted that TEAD is the primary mediator of the growth-promoting and tumorigenic potential of YAP and TAZ (pathways reviewed in Yu et al., 2015; Holden and Cunningham, 2018).

[0004] Thus, hyperactivation of YAP and / or TAZ (and subsequent hyperactivity of the YAP / TAZ-TEAD transcription complex) is commonly observed in several human cancers, as manifested by elevated levels and nuclear localization of YAP / TAZ in many tumors, including breast, lung (e.g., non-small cell; NSCLC), ovarian, colorectal, pancreatic, prostate, gastric, esophageal, liver, and bone tumors (sarcomas) (Steinhardt et al., 2008; Harvey et al., 2013; Moroishi et al., 2015; Zanconato et al., 2016 (extensively reviewed), and references therein).

[0005] Although genetic alterations of core Hippo pathway components have so far been detected with limited frequency in primary samples, the most prominent cancer malignancy with inactivating mutations of NF2 or Lats1 / 2 and with YAP / TEAD hyperactivity is malignant pleural mesothelioma (MPM) (reviewed in Sekido, 2018). Similarly, several human tumors are characterized by amplification of YAP at locus 11q22.1 (e.g., hepatocellular carcinoma, medulloblastoma, esophageal squamous cell carcinoma), amplification of TAZ (WWTR1) at locus 3q25.1 (e.g., rhabdomyosarcoma, triple-negative breast cancer), or gene fusions involving YAP or TAZ (epithelioid hemangioendothelioma, ependymal tumors) (reviewed in Yu et al., 2015 and references therein). As in the case of MPM, such tumors are also expected to depend on their elevated YAP / TAZ-TEAD activity.

[0006] As the most terminal effector branch point of Hippo pathway, the disruption of YAP / TAZ-TEAD PPI is expected to abolish the oncogenic potential of this complex.The compounds of the present invention are designed and optimized to bind to TEAD and selectively disrupt the interaction of TEAD with YAP and TAZ, which is believed to provide drugs useful for the treatment of the above-mentioned cancers.These cancers may be characterized in particular by some of the abnormalities described (but are not limited to them).

[0007] In particular, tumor cells with activated YAP / TAZ-TEAD exhibit resistance to chemotherapeutic drugs, possibly related to YAP / TAZ conferring cancer stem cell-like properties. Moreover, as reported from the results of various genetic and pharmacological screens, YAP / TAZ-TEAD activation also confers resistance to molecular targeted therapies, such as BRAF, MEK, or EGFR inhibitors (Kapoor et al., 2014; Shao et al., 2014; Lin et al., 2015). This in turn suggests that inhibiting YAP / TAZ-TEAD activity - in parallel or sequentially with other cancer treatments - could provide beneficial therapeutic impact by reducing the growth of tumors resistant to other treatments.

[0008] Inhibition of YAP / TAZ-TEAD activity upon PPI disruption with the above mentioned LMW compounds can also blunt tumor escape from immune surveillance. This is e.g. revealed by reported data on YAP promoting the expression of the chemokine CXCL5 leading to the recruitment of myeloid cells that suppress T cells (Wang et al., 2016). It has also been demonstrated that YAP in Tregs (regulatory T cells) supports FOXP3 expression via activin signaling and Treg function. Thus, YAP deficiency leads to dysfunctional Tregs that can no longer suppress antitumor immunity. Thus, selective inhibition of YAP / TEAD activity can contribute to supporting antitumor immunity by preventing Treg function (Ni et al., 2018). Recent literature also suggests that YAP upregulates PD-L1 expression and by this mechanism directly mediates the evasion of cytotoxic T cell immune responses, e.g. in BRAF inhibitor-resistant melanoma cells (Kim et al., 2018). For therapeutic purposes, the above-mentioned YAP / TAZ-TEAD PPI compounds can be used in combination with cancer immunotherapy drugs, such as immune checkpoint inhibitors (e.g., anti-PD-1 antibodies).

[0009] The TEAD inhibitor 4-((2S,4S)-5-chloro-6-fluoro-2-phenyl-2-((S)-pyrrolidin-2-yl)-2,3-dihydrobenzofuran-4-yl)-5-fluoro-6-(2-hydroxyethoxy)-N-methylnicotinamide (Compound A), and methods for preparing said inhibitors, are described in International Patent Application No. PCT / IB2021 / 052136, which is incorporated by reference.

[0010] Nephrotoxicity, particularly tubular degeneration, is believed to be a safety / toxicity risk associated with some TEAD inhibitors, especially in the case of long-term treatment.Therefore, there remains a need in the art for dosing regimens of TEAD inhibitors that provide improved safety profiles.

[0011] See, for example: Yu, FX., Zhao, B. and Guan, K.-L. (2015). Hippo pathway in organ size control, tissue homeostasis and cancer. Cell, 163, 811-828. Holden, JK and Cunningham, CN (2018).Targeting the Hippo pathway and cancer through the TEAD family of transcription factors.Cancers(Basel),10,E81. Steinhardt, AA, Gayyed, MF, Klein, AP, Dong, J., Maitra, A., Pan, D., Montgomery, EA, Anders, RA (2008). Expression of Yes-associated protein in common solid tumors. Hum. Pathol., 39, 1582-1589. Harvey,K.F.,Zhang,X., and Thomas,D.M.(2013).The Hippo pathway and human cancer.Nat.Rev.Cancer,13,246-257. Moroishi,T.,Hansen,C.G., and Guan,K.-L.(2015).Nat.Rev.Cancer,15,73-79. Zanconato,F.,Cordenonsi,M., and Piccolo,S.(2016).YAP / TAZ at the roots of cancer.Cancer Cell,29,783-803. Sekido,Y.(2018).Cancers(Basel),10,E90. Kapoor,A.,Yao,W.,Ying,H.,Hua,S.,Liewen,A.,Wang,Q.,Zhong,Y.,Wu,C.J.,Sadanandam,A.,Hu,B.et al.(2014).Yap1 activation enables bypass of oncogenic Kras addiction in pancreatic cancer.Cell,158,185-197. Shao,D.D.,Xue,W.,Krall,E.B.,Bhutkar,A.,Piccioni,F.,Wang,X.,Schinzel,A.C.,Sood,S.,Rosenbluh,J.,Kim,J.W.,et al.(2014).KRAS and YAP1 converge to regulate EMT and tumor survival.Cell,158,171-184. Lin,L.,Sabnis,A.J.,Chan,E.,Olivas,V.,Cade,L.,Pazarentzos,E.,Asthana,S.,Neel,D.,Yan,J.J.,Lu,X.et al.(2015).The Hippo effector YAP promotes resistance to RAF- and MEK-targeted cancer therapies.Nat.Genet.,47,250-256. Wang, G., Lu, Ni, X., Tao, J., Barbi, J., Chen, Q., Park BV, Li, Z., Zhang, N., Lebid, A., Ramaswamy, A., Wei, P., et al. (2018). YAP is essential for Treg-mediated suppression of antitumor immunity. Cancer Discov., 8, 1026-1043. Kim, MH, Kim, CG, Kim, SK, Shin, SJ, Choe, EA, Park, SH, Shin, EC, and Kim, J. (2018). Cancer Immunol Res., 6, 255-266. Summary of the Invention

[0012] One of the goals in the development of TEAD inhibitors is to find a dosing regimen that ensures efficacy while at the same time reducing the amount of adverse side effects (eg, nephrotoxicity).

[0013] Surprisingly, it has been found that the dosing schedule of the present invention is associated with reduced nephrotoxicity as compared to a daily continuous dosing schedule.

[0014] Specifically, the present invention provides the following aspects, advantageous features and specific embodiments, taken alone or in combination, as recited in the following numbered embodiments:

[0015] Embodiment 1. A TEAD inhibitor, or a pharma- ceutically acceptable salt thereof, for use in the treatment of cancer, wherein the TEAD inhibitor, or a pharma- ceutically acceptable salt thereof, is administered on each of the first three days of a seven day treatment cycle, and wherein the treatment comprises at least two treatment cycles.

[0016] Embodiment 2. A method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a TEAD inhibitor, or a pharma- ceutically acceptable salt thereof, on each of the first three days of a seven-day treatment cycle, and wherein the treatment comprises at least two treatment cycles.

[0017] Embodiment 3. A method of reducing albuminuria and / or nephrotoxicity in a subject undergoing treatment with a TEAD inhibitor, or a pharma- ceutically acceptable salt thereof, comprising administering to the subject a therapeutically effective amount of said TEAD inhibitor, or a pharma- ceutically acceptable salt thereof, on each of the first three days of a seven-day treatment cycle, and wherein said treatment comprises at least two treatment cycles.

[0018] Embodiment 4. The TEAD inhibitor or a pharma- ceutically acceptable salt thereof for use in the treatment of cancer according to embodiment 1, or the method according to embodiment 2 or embodiment 3, wherein the TEAD inhibitor is a YAP / TAZ-TEAD protein / protein interaction inhibitor or a pharma- ceutically acceptable salt thereof.

[0019] Embodiment 5. A TEAD inhibitor or a pharma- ceutically acceptable salt thereof for use in the treatment of cancer according to embodiment 1 or embodiment 4, or a method according to any one of embodiments 2 to 4, wherein the TEAD inhibitor or a salt thereof is 4-((2S,4S)-5-chloro-6-fluoro-2-phenyl-2-((S)-pyrrolidin-2-yl)-2,3-dihydrobenzofuran-4-yl)-5-fluoro-6-(2-hydroxyethoxy)-N-methylnicotinamide or a pharma- ceutically acceptable salt thereof.

[0020] Embodiment 6. The TEAD inhibitor or a pharma- ceutically acceptable salt thereof for use in the treatment of cancer according to any one of embodiments 1, 4, and 5, or the method according to any one of embodiments 2 to 5, wherein the daily dose on each day of administration is 15 mg to 100 mg.

[0021] Embodiment 6a. The TEAD inhibitor or a pharma- ceutically acceptable salt thereof for use in the treatment of cancer according to any one of embodiments 1, 4, and 5, or the method according to any one of embodiments 2 to 5, wherein the daily dose on each said administration day is 15 mg to 500 mg, for example 60 mg to 300 mg, for example 60 mg to 240 mg.

[0022] Embodiment 7. The TEAD inhibitor or a pharma- ceutically acceptable salt thereof for use in the treatment of cancer according to embodiment 6, or the method according to embodiment 6, wherein the daily dose on each day of administration is 15, 30, 45, 60, 75 mg, 90 mg, or 100 mg.

[0023] Embodiment 8. A TEAD inhibitor or a pharma- ceutically acceptable salt thereof for use in the treatment of a cancer according to any one of embodiments 1 and 4 to 7, or a method according to any one of embodiments 2 to 7, wherein the cancer is a TEAD-dependent cancer (e.g., the cancer has Hippo pathway dysregulation) or a solid tumor with an NF2 / LATS1 / LATS2 mutation.

[0024] Embodiment 9. The TEAD inhibitor or a pharma- ceutically acceptable salt thereof for use in the treatment of a cancer according to any one of embodiments 1 and 4 to 8, or the method according to any one of embodiments 2 to 8, wherein the cancer is selected from breast cancer, lung cancer, ovarian cancer, renal cancer, uterine cancer, colorectal cancer, mesothelioma, e.g., malignant pleural mesothelioma, pancreatic cancer, prostate cancer, gastric cancer, esophageal cancer, liver cancer, medulloblastoma, head and neck cancer, sarcoma, epithelioid hemangioendothelioma, ependymal tumors, and bone cancer, e.g., the cancer is mesothelioma, e.g., the cancer is malignant pleural mesothelioma.

[0025] The dosing regimen of the present invention provides reduced nephrotoxicity as illustrated in the figures and examples.

[0026] In the following the invention will be described in detail with reference to the accompanying drawings. [Brief description of the drawings]

[0027] [Figure 1]1A-E show (A) antitumor activity, (B) survival rate, and (C-E) urinary kidney injury marker assessment of Compound A or vehicle control in the MSTO-211H sc xenograft rat model using a weekly dose of 420 mg / kg (po) according to one of four different Compound A dosing schedules. [Diagram 2] Relative antitumor efficacy and tolerability of Compound A using daily or intermittent schedules in nude rats bearing (A) MSTO-211H and (B) NCI-H226 mesothelioma tumors. Values ​​are mean ± SEM; sample size: n=5. *p<0.05, significant inhibition compared to vehicle control group (one-way ANOVA with Dunnett's multiple comparison test for tolerability data). (C) Urinary kidney injury marker evaluation of Compound A, combining results from two experiments from MSTO-211H and NCI-H226 sc xenograft rat models, values ​​are mean ± SEM; sample size: n=4-6. *p<0.05, **p<0.01, ***p<0.001 significant inhibition compared to vehicle control group (one-way ANOVA with Dunnett's multiple comparison test). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0028] As explained above, one of the goals in the development of TEAD inhibitors is to find a dosing regimen that ensures efficacy while at the same time reducing the amount of adverse side effects (e.g., nephrotoxicity).

[0029] Thus, the present invention provides a TEAD inhibitor or a pharma- ceutically acceptable salt thereof for use in the treatment of cancer, administered on each of the first three days of a seven-day treatment cycle, and comprising at least two treatment cycles. As illustrated in the examples and figures, this has been found to be equivalent in efficacy to QD dosing, while at the same time providing improved survival and reduced nephrotoxicity, thus providing a broader therapeutic window.

[0030] It should be understood that "administered on each of the first 3 days of a 7-day treatment cycle" means that the TEAD inhibitor, or a pharma- ceutically acceptable salt thereof, is administered on each of the first 3 days of a 7-day treatment cycle, and is not administered on the subsequent 4 days of the 7-day treatment cycle.

[0031] Preferably, at least two treatment cycles are consecutive, i.e., the second treatment cycle immediately follows the first treatment cycle. Thus, for example, the present invention provides a method for treating a patient having a disease comprising the following: Days 1–3: TEAD inhibitors are administered daily; Days 4–7: No TEAD inhibitors were administered; Days 8-10: TEAD inhibitors are administered daily; and Days 11-14: No TEAD inhibitors were administered Includes.

[0032] In this example, days 1-3 and days 8-10 are administration days. Thus, "administration days" refers to any day on which a TEAD inhibitor is administered to a patient.

[0033] If present, the third (fourth, etc.) treatment cycle preferably immediately follows the previous treatment cycle. Thus, in embodiments where there are three treatment cycles, the present invention provides the following: Days 1–3: TEAD inhibitors are administered daily; Days 4–7: No TEAD inhibitors were administered; Days 8–10: TEAD inhibitors are administered daily; Days 11–14: No TEAD inhibitors were administered; Days 15-17: TEAD inhibitor is administered daily; and Days 18-21: No TEAD inhibitors were administered Includes.

[0034] In an embodiment, there are three or more treatment cycles, such as four or more treatment cycles, such as five or more treatment cycles, such as six or more treatment cycles, such as eight or more treatment cycles, such as ten or more treatment cycles.

[0035] The TEAD inhibitors can exist as free molecules or as pharma- ceutically acceptable salts thereof. Preferably, the TEAD inhibitors are present in free form (i.e., not as salts) and are optionally solvated.

[0036] The term "TEAD inhibitor" refers to a compound having an IC50 of less than 10 μM, preferably less than 1 μM, more preferably less than 0.1 μM, and even more preferably less than 0.01 μM as measured by Time Resolved Fluorescence Energy Transfer (TR-FRET) measurement. 50 The present invention represents any compound that inhibits the TEAD protein.

[0037] As used herein, the term "YAP / TAZ-TEAD PPII" or "YAP / TAZ-TEAD protein-protein interaction inhibitor" or "YAP / TAZ-TEAD PPI inhibitor" refers to a compound that is capable of inhibiting the interaction between i) TEAD and ii) YAP and / or TAZ, e.g., by binding to TEAD and thereby selectively disrupting the interaction of TEAD with YAP and / or TAZ. In one embodiment, IC 50 has an IC of less than 10 μM, preferably less than 1 μM, more preferably less than 0.1 μM, and even more preferably less than 0.01 μM as measured by Time Resolved Fluorescence Energy Transfer (TR-FRET) measurement. 50 It is.

[0038] As used herein, the term "daily dose" refers to the total dosage administered to an individual in a 24-hour day. When referring to a dose of a TEAD inhibitor, e.g., in mg (milligrams), herein, the (equivalent) amount of the TEAD inhibitor in free form (i.e., excluding, e.g., salts or co-crystal partners, as well as any solvents present) is referred to.

[0039] As used herein, the term "salt" refers to an acid addition or base addition salt of the conjugate of the present invention. "Salt" specifically includes "pharmaceutically acceptable salts". The term "pharmaceutically acceptable salts" refers to salts that retain the biological effectiveness and properties of the conjugate of the present invention and are typically not biologically or otherwise undesirable. In many cases, the conjugate of the present invention is capable of forming acid and / or base salts by virtue of the presence of amino and / or carboxyl groups or groups similar thereto. When both basic and acidic groups are present in the same molecule, the conjugate of the present invention can also form intramolecular salts, e.g., zwitterionic molecules.

[0040] Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids.

[0041] Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.

[0042] Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid, and the like.

[0043] Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.

[0044] Inorganic bases from which salts can be derived include, for example, ammonium salts and metals of the periodic table, groups 1 to 12. In certain embodiments, salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include the ammonium, potassium, sodium, calcium, and magnesium salts.

[0045] Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, basic ion exchange resins, etc. Certain organic amines include isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine.

[0046] In another aspect, the present invention provides an acid salt, such as acetate, ascorbate, adipate, aspartate, benzoate, besylate, bromide / hydrobromide, bicarbonate / carbonate, bisulfate / sulfate, camphorsulfonate, caprate, chloride / hydrochloride, chlortheophyllonate, citrate, ethanedisulfonate, fumarate, gluceptate, gluconate, glucuronate, glutamate, glutarate, glycolate, hippurate, hydroiodide / iodide, isethionate, lactate, lactobionate, The conjugates of the invention are provided in the form of a salt, lauryl sulfate, malate, maleate, malonate, mandelate, mesylate, methylsulfate, mucate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, polygalacturonate, propionate, sebacate, stearate, succinate, sulfosalicylate, sulfate, tartrate, tosylate, triphenylacetate, trifluoroacetate, or xinafoate salt.

[0047] Preferably, drug administration is by oral delivery, ie, oral administration, orally (po).

[0048] Preferably, the drug is provided in an oral dosage form, more preferably in the form of a solid oral dosage form, such as a capsule or tablet.

[0049] Preferably, the drug is taken with a glass of water and without chewing the capsule or tablet.

[0050] If a patient is assigned to a dose level where multiple capsules / tablets are to be taken, the capsules / tablets should be taken consecutively with as little time between each dose as possible, for example within 5 minutes.

[0051] Preferably, the drug is administered at about the same time each day of administration. Preferably, the drug is administered once a day each day of administration. More preferably, the drug is administered in the morning.

[0052] Preferably, the drug is administered in the fasted state, ie, at least 1 hour before or 2 hours after a meal.

[0053] As used herein, the term "drug" refers to a TEAD inhibitor, or a pharma- ceutically acceptable salt thereof.

[0054] The TEAD inhibitor can be delivered to a subject in the form of a pharmaceutical composition.

[0055] The oral dosage forms to be used are, for example, tablets, capsules, sachets, micropellets, granules, etc. The oral dosage forms may contain, in addition to Mdm2i, further conventional carriers or excipients used in medicine. Examples of such carriers or excipients include, but are not limited to, disintegrants, binders, lubricants, flow agents, stabilizers, and fillers, diluents, colorants, flavors, and preservatives. Those skilled in the art can select one or more of the above mentioned carriers with respect to the particular desired properties of the dosage form by routine experimentation and without undue burden. The amount of each carrier used may vary within the ranges conventional in the art. The following references disclose techniques and excipients used to formulate oral dosage forms: See, The Handbook of Pharmaceutical Excipients, 4th edition, Rowe et al., Eds., American Pharmaceuticals Association (2003); and Remington: the Science and Practice of Pharmacy, 20th edition, Gennaro, Ed., Lippincott Williams & Wilkins (2003). Dosage forms are prepared, for example, by blending, granulating, compressing, compacting, filling, sieving, mixing, and / or tabletting.

[0056] As used herein, the term "subject" refers to an animal. Preferably, the animal is a mammal. The subject refers to, for example, a primate (e.g., a human), cow, sheep, goat, horse, dog, cat, rabbit, rat, mouse, fish, bird, etc. In a preferred embodiment, the subject is a human.

[0057] As used herein, the term "TEAD-dependent cancer" refers to any cancer in which TEAD (i.e., TEAD1, TEAD2, TEAD3, and / or TEAD4) or a mutant or variant thereof is known to be associated, e.g., a cancer in which the Hippo pathway is genetically altered.

[0058] As used herein, the terms "inhibit," "inhibition," or "inhibiting" refer to the alleviation or suppression of a given condition, symptom, or disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process.

[0059] As used herein, the terms "treat," "treating," or "treatment" of any disease or disorder refers to alleviating or ameliorating the disease or disorder (i.e., slowing or halting the onset of the disease, or at least one of its clinical symptoms); or alleviating or ameliorating at least one physical parameter or biomarker associated with the disease or disorder (including those that may not be discernible to the patient).

[0060] As used herein, the terms "prevent," "preventing," or "prevention" of any disease or disorder refers to prophylactic treatment of the disease or disorder; or delaying the onset or progression of the disease or disorder.

[0061] As used herein, a subject is "in need of" a treatment if such subject would benefit biologically, medically, or in quality of life from such treatment.

[0062] As used herein, the term "reducing nephrotoxicity" includes, inter alia, a reduction in urinary kidney injury biomarkers NGAL and / or KIM-1.

[0063] The term "therapeutically effective amount" of a compound of the present disclosure refers to an amount of a compound of the present disclosure that, when administered to a subject, is effective to (1) at least partially alleviate, inhibit, prevent, and / or ameliorate a condition or disorder or disease that is (i) associated with overactivation of the YAP / TAZ-TEAD complex, (ii) mediated by YAP overexpression and / or YAP amplification, (iii) associated with YAP activity, or (iv) characterized by YAP (normal or abnormal) activity; or (2) reduce or inhibit the interaction of YAP and / or TAZ with TEAD. In another non-limiting embodiment, the term "therapeutically effective amount" refers to an amount of a compound of the present disclosure that, when administered to a cell, or tissue, or non-cellular biological material, or medium, is effective to at least partially reduce or inhibit the interaction of YAP and / or TAZ with TEAD.

[0064] As used herein, the terms "a," "an," "the," and similar terms as used in the context of the present invention (particularly in the context of the claims) are to be construed to encompass both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.

[0065] The term "comprising" encompasses "comprising" as well as "consisting of." For example, a composition comprising X may consist exclusively of X or may include additional, e.g., X and Y.

[0066] In one embodiment, the TEAD inhibitor is a YAP / TAZ-TEAD protein / protein interaction inhibitor, or a pharma- ceutically acceptable salt thereof, which functions by disrupting protein-protein interactions between YAP1 / WWTR1 and all four TEAD isoforms, thereby abolishing the transcriptional activity of a complex that controls key genes involved in proliferation and survival, as described below. Dupont S,Morsut L,Aragona M,Enzo E,Giulitti S,Cordenonsi M,Zanconato F,Le Digabel J,Forcato M,Bicciato S,et al.(2011).Role of YAP / TAZ in mechanotransduction.Nature 474,179-183, Lai D, Ho KC, Hao Y and Yang X(2011).Taxol resistance in breast cancer cells is mediated by the hippo pathway component TAZ and its downstream transcriptional targets Cyr61 and CTGF.Cancer Res.71,2728-2738, and Zhao B,Ye X,Yu J,Li L,Li W,Li S,et al.(2008)TEAD mediates YAP-dependent gene induction and growth control.Genes Dev.;22(14):1962-71.

[0067] In one embodiment, the TEAD inhibitor is 4-((2S,4S)-5-chloro-6-fluoro-2-phenyl-2-((S)-pyrrolidin-2-yl)-2,3-dihydrobenzofuran-4-yl)-5-fluoro-6-(2-hydroxyethoxy)-N-methylnicotinamide, or a pharma- ceutically acceptable salt thereof.

[0068] In one embodiment, the daily dose of a TEAD inhibitor (e.g., 4-((2S,4S)-5-chloro-6-fluoro-2-phenyl-2-((S)-pyrrolidin-2-yl)-2,3-dihydrobenzofuran-4-yl)-5-fluoro-6-(2-hydroxyethoxy)-N-methylnicotinamide) is from 15 mg to 100 mg, for example from 15 mg to 75 mg, for example 15 mg, 30 mg, 45 mg, 60 mg, 75 mg, 90 mg, or 100 mg (expressed with respect to the free drug).

[0069] In an alternative embodiment, the TEAD inhibitor is: [ka] This inhibitor is disclosed in WO 2022 / 159986 and WO 2020 / 243415.

[0070] In one embodiment, the cancer is a TEAD-dependent cancer or a cancer selected from breast cancer (e.g., triple-negative breast cancer), lung cancer, ovarian cancer, renal cancer, uterine cancer, colorectal cancer, malignant pleural mesothelioma, pancreatic cancer, prostate cancer, gastric cancer, esophageal cancer, liver cancer, medulloblastoma, head and neck cancer, sarcoma, epithelioid hemangioendothelioma, ependymal tumors, and bone cancer.

[0071] In one embodiment, the TEAD inhibitor is administered together with an additional pharma- ceutically active drug (combination partner). If a combination partner is present, the TEAD inhibitor is preferably provided with instructions for combined use. The compounds in the combination can be administered completely separately. These compounds can be in completely separate pharmaceutical dosage forms. The combination partners can be pharmaceutical compositions sold independently of each other, where appropriate instructions for their combined use, for simultaneous or sequential use to be jointly active, are provided in the packaging accessories, such as leaflets, or in other information provided, for example, to physicians and medical staff (e.g., oral communication, written communication, etc.). The TEAD inhibitor and the other pharma-ceutically active drug can be provided as a fixed or non-fixed combination of active ingredients. The term "fixed combination" means that both of these active ingredients are administered to the patient at the same time in the form of a single entity or dosage. In other words: these active ingredients are present in one dosage form, for example in one tablet or in one capsule. The term "non-fixed combination" means that both of these active ingredients are administered to a patient as separate entities, simultaneously, in parallel or sequentially, without any specific time limit, where such administration provides therapeutically effective levels of the two compounds in the patient's body.

[0072] The synthesis of compound A: (4-((2S,4S)-5-chloro-6-fluoro-2-phenyl-2-((S)-pyrrolidin-2-yl)-2,3-dihydrobenzofuran-4-yl)-5-fluoro-6-(2-hydroxyethoxy)-N-methylnicotinamide) was first described in PCT / IB2021 / 052136 (WO 2021 / 186324), the contents of which are incorporated by reference. EXAMPLES

[0073] The following examples illustrate (but are not intended to limit) the present invention.

[0074] Example 1 Antitumor activity, survival rate, and urinary kidney injury marker evaluation of Compound A in MSTO-211H sc xenograft rat model Female nude rats bearing MSTO-211H subcutaneous xenografts were treated with Compound A or vehicle control for a total of 4 weeks. All Compound A-treated rats were divided into 4 separate cohorts: i) 60mg / kg QD ii) 84mg / kg, 5 days on / 2 days off iii) 120mg / kg, 1 day on / 1 day off iv) 140mg / kg, 3 days on / 4 days off All rats were given a total weekly dose of 420 mg / kg of Compound A (po), split into two doses.

[0075] Data were collected from rat samples regarding antitumor activity (Figure 1A), survival rate (Figure 1B), and urinary kidney injury marker assessment, namely NGAL (Figure 1C), KIM-1 (Figure 1D), and albumin (Figure 1E).

[0076] A) Antitumor activity of Compound A: Some of the vehicle tumors underwent spontaneous regression when the rat immune system recovered from sublethal radiation. Values ​​are mean ± SEM; sample size, (n = 3-4 rats / group). Compound A dosing regimens were all similarly effective in reducing tumor volume.

[0077] B) Animal survival rate * p<0.05, significant inhibition compared to vehicle control (log-rank Mantel Cox test). Compound A toxicity was shown to be schedule dependent, as demonstrated by the finding that a weekly dose of 420 mg / kg / week was lethal when given on a 60 mg / kg QD schedule, but when the same weekly dose was administered on a 3 days on / 4 days off schedule with extended dosing breaks, all rats survived and NGAL and KIM-1 renal urinary biomarker levels were lower, suggesting less renal tubular damage.

[0078] Urine specimens. C) NGAL, D) KIM-1, and E) albumin were quantified from rat samples collected on the indicated days. Sample sizes n=1-4 / group, mean ± SEM are represented. Upper limit of quantification (LOQ) is indicated for urinary albumin levels. For the 60 mg / kd QD cohort, elevated urinary renal markers were observed, which led to animals being discontinued from continued treatment after 14-18 days. Analysis of urinary quantification of NGAL, KIM-1, and albumin revealed that renal tubular damage and protein-losing nephropathy were dose-limiting toxicities in nude rats.

[0079] Example 2 Relative antitumor activity of Compound A using daily or intermittent schedules in nude rats bearing MSTO-211H and NCI-H226 mesothelioma tumors. A 3- or 4-week efficacy study of treatment with Compound A administered po using a QD (solid line) or 3 days on / 4 days off intermittent schedule (dotted line) was conducted in the MSTO-211H and NCI-H226 rat models using weekly doses of 105 or 210 mg / kg. Female nude rats bearing MSTO-211H or NCI-H226 sc xenografts were treated with vehicle control or Compound A. Compound A-treated rats were divided into four separate cohorts: i) 15mg / kg qd ii) 35mg / kg, 3 days on / 4 days off iii) 30 mg / kg qd; and iv) 70mg / kg, 3 days on / 4 days off was divided into.

[0080] Efficacy (Figure 2A,B, left) and tolerability (Figure 2A,B, right) data were collected. The use of intermittent dosing did not affect antitumor efficacy in MSTO-211H or NCI-H226 mesothelioma tumor models compared to QD dosing. A total weekly dose of 210 mg / kg was non-lethal and well tolerated for all schedules, including 30 mg / kg QD (unlike the 60 mg / kg QD dosing regimen tested in Example 1). However, as shown in Figure 2C, the 70 mg / kg 3 days on / 4 days off intermittent dosing schedule still had a reduction in albuminuria and urinary kidney injury markers, NGAL and KIM-1, to or near baseline levels compared to the 30 mg / kg QD schedule, indicating that even at tolerable dosing levels, the 3 days on / 4 days off schedule is likely to result in reduced kidney toxicity compared to daily dosing.

[0081] Example 3 A study will be conducted to characterize the safety and tolerability of Compound A in patients with mesothelioma and other solid tumors with Hippo pathway dysregulation to evaluate the safety, tolerability, PK, and PD of Compound A. In this study, Compound A will be administered on each of the first 3 days of a 7-day treatment cycle and treatment will include at least two treatment cycles.

Claims

1. 1. A composition comprising a TEAD inhibitor or a pharmaceutically acceptable salt thereof for use in treating cancer, wherein the TEAD inhibitor or a pharmaceutically acceptable salt thereof is administered on each of the first three days of a seven-day treatment cycle, and the treatment comprises at least two treatment cycles.

2. 1. A composition comprising a TEAD inhibitor or a pharmaceutically acceptable salt thereof for use in a method for reducing albuminuria and / or nephrotoxicity in a subject undergoing treatment with a TEAD inhibitor or a pharmaceutically acceptable salt thereof, the method comprising administering to the subject a therapeutically effective amount of the TEAD inhibitor or a pharmaceutically acceptable salt thereof on each of the first three days of a seven-day treatment cycle, and the treatment comprising at least two treatment cycles.

3. The composition of claim 1, wherein the TEAD inhibitor is a YAP / TAZ-TEAD protein / protein interaction inhibitor or a pharmaceutically acceptable salt thereof.

4. The composition according to claim 1, wherein the TEAD inhibitor or a salt thereof is 4-((2S,4S)-5-chloro-6-fluoro-2-phenyl-2-((S)-pyrrolidin-2-yl)-2,3-dihydrobenzofuran-4-yl)-5-fluoro-6-(2-hydroxyethoxy)-N-methylnicotinamide or a pharmaceutically acceptable salt thereof.

5. 2. The composition of claim 1, wherein the daily dose on each day of administration is 15 mg to 500 mg.

6. The composition of claim 5, wherein the daily dose on each day of administration is 15 mg to 100 mg.

7. 6. The composition of claim 5, wherein the daily dose on each day of administration is 15, 30, 45, 60, 75 mg, 90 mg, or 100 mg.

8. The composition of claim 1, wherein the cancer is a TEAD-dependent cancer or a solid tumor with an NF2 / LATS1 / LATS2 mutation.

9. 9. The composition of any one of claims 1 to 8, wherein the cancer is selected from breast cancer, lung cancer, ovarian cancer, renal cancer, uterine cancer, colorectal cancer, mesothelioma, e.g., malignant pleural mesothelioma, pancreatic cancer, prostate cancer, gastric cancer, esophageal cancer, liver cancer, medulloblastoma, head and neck cancer, sarcoma, epithelioid hemangioendothelioma, ependymal tumor, and bone cancer, e.g., the cancer is mesothelioma, e.g., the cancer is malignant pleural mesothelioma.

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