Methods of treating cancer

Abstract

The present disclosure provides, among other things, methods of treating diseases, disorders, or conditions using an inhibitor of KAT6A and KAT6B, wherein the inhibitor of KAT6A and KAT6B is Compound 1 or a pharmaceutically acceptable salt thereof.

Description

Attorney Docket No. 2012034-0398METHODS OF TREATING CANCER CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] The present application claims priority to and the benefit of (i) U. S. Provisional Patent Application No. 63 / 746,217, filed January 16. 2025, and (ii) U. S. Provisional Patent Application No. 63 / 795,155, filed April 25, 2025, the entire contents both of which are hereby incorporated by reference in their entireties.BACKGROUND

[0002] Lysine acetyl transferases (KATs) have emerged as a promising target for treatment of breast cancer in recent years. Enzymes KAT6A and KAT6B are members of the MYST family of protein acetyltransferases, and play an important role in transcription, maintenance, and regulation of hematopoietic and neural stem cells, skeletogenesis, meiosis, and cell cycle progression. Olbromski, et al.. Nature Scientific Reports (2024) 14:26935. Dysregulation of KAT6A and KAT6B is implicated in a number of cancers, including breast, prostate, liver, gastrointestinal, endometrium, and lung. Inhibition of KAT6 enzymes blocks histone acetylation and downregulates transcription of proliferation-associated genes. Currently, there are no approved therapies that modulate both KAT6A and KAT6B to treat these diseases.SUMMARY

[0003] There remains a need for improved therapies useful in treating cancer, such as, for example, those associated with inhibition of both KAT6A and KAT6B. The present disclosure encompasses the surprising and unexpected discovery that Compound 1:Compound 1,or a pharmaceutically acceptable salt thereof, is, among other things, useful in treating diseases, disorders, and conditions such as those mediated by KAT6A and / or KAT6B, for example, by inhibiting both KAT6A and KAT6B. That is to say, that the present disclosure provides Page 1 of 6913238167vlAttorney Docket No. 2012034-0398Compound 1, or a pharmaceutically acceptable salt thereof, as a dual inhibitor of KAT6A / B. Additionally, Compound 1, or a pharmaceutically acceptable salt thereof, demonstrates, among other things, efficacy in both in vitro and in vivo models in treating certain cancers, including, but not limited to, ovarian, prostate, and non-small cell lung cancer (“NSCLC”). Furthermore, Compound 1 has been found to be particularly effective in treating platinum resistant cancers. Compound 1 also has been found to exhibit surprising efficacy in treating certain cancers as both a monotherapy and as a component in combination therapies.

[0004] In one aspect, provided is a method of treating a disease, disorder, or condition such as, a disease, disorder or condition mediated by K. AT6A and / or K. AT6B, in a subject in need thereof, by inhibiting KAT6A and / or KAT6B, the method comprising administering to the subject an effective amount of Compound 1,I / 0\ / ^z0 / AO n 0'NHCompound 1,or a pharmaceutically acceptable salt thereof.

[0005] In some embodiments, provided is a method of treating a disease, disorder, or condition responsive to inhibition of KAT6A and / or KAT6B, such as, for example, those diseases, disorders or conditions responsive to inhibition of both KAT6A and KAT6B, or responsive to inhibition of KAT6B, in a subject in need thereof, comprising administering to the subject an effective amount of Compound 1, or a pharmaceutically acceptable salt thereof.

[0006] In some embodiments, provided is a method of treating a solid cancer that is responsive to treatment with a dual inhibitor of both KAT6A and KAT6B in a patient in need thereof, the method comprising administering to the subject an effective amount of Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, provided is a method of treating a solid cancer that is responsive to treatment with an inhibitor of KAT6B in a patient in need thereof, the method comprising administering to the subject an effective amount of Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the cancer is lung cancer, such as, for example, non-small cell lung cancer. In one or more other embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is breast cancer.Page 2 of 6913238167vlAttorney Docket No. 2012034-0398

[0007] In some embodiments, the present disclosure provides a method of treating a solid cancer, such as, for example, non- small-cell lung cancer, in a subject in need thereof, the method comprising administering to the subject an effective amount of Compound 1.VQ, A0 n0'NHCompound 1,or a pharmaceutically acceptable salt thereof. In some other embodiments of the above method, the cancer is prostate cancer. In yet some further embodiments of the method of treating a solid cancer, the cancer is ovarian cancer.

[0008] In some embodiments, the present disclosure provides a method of inhibiting tumor growth in a subject in need thereof, wherein the tumor is an ovarian cancer tumor, a prostate cancer tumor, or a non-small-cell lung cancer tumor, the method comprising administering to the subject, an effective amount of Compound 1,Compound 1,or a pharmaceutically acceptable salt thereof.

[0009] In some embodiments, the present disclosure provides a method of treating a platinum-resistant ovarian cancer, comprising administering to a subject in need thereof an effective amount of Compound 1,Compound 1or a pharmaceutically acceptable salt thereof.Page 3 of 6913238167vlAttorney Docket No. 2012034-0398BRIEF DESCRIPTION OF THE DRAWINGS

[0010] FIGs. 1A-1E are plots illustrating percent inhibition of KAT6A (FIG.1A), KAT6B (FIG. 1B), KAT7 (FIG. 1C), KAT5 (FIG. 1D), and KAT8 (FIG.1E) by Compound 1. KAT6A, KAT6B, KAT7, KAT5, and KAT8 were incubated with biotin-labelled histone 4, acetyl CoA and a europium-labelled anti-acetyl lysine antibody. HAT activity was measured by TR-FRET. Data shown are representative of experiments performed at least three separate times.

[0011] FIGs. 2A-2F: FIG. 2A is a plot illustrating decrease of proliferation of VCaP cells (prostate cancer) after exposure to varying concentrations of Compound 1. FIG. 2B is a plot illustrating decrease of proliferation of LCLC-97TM1 cells (lung cancer / NSCLC) after exposure to varying concentrations of Compound 1. FIG. 2C is a plot illustrating decrease of proliferation of OAW28 cells (ovarian cancer) after exposure to varying concentrations of Compound 1. FIG.2D is a plot illustrating decrease of proliferation of OVCAR3 cells (ovarian cancer) after exposure to varying concentrations of Compound 1. FIG. 2E is a plot illustrating decrease of proliferation of LNCaP (FGC) cells (prostate cancer) after exposure to varying concentrations of Compound 1.FIG. 2F is a plot illustrating decrease of proliferation of NCI-H1648 cells (lung cancer / NSCLC) after exposure to varying concentrations of Compound 1.

[0012] FIGs. 3A-3D: FIG. 3A is a plot illustrating the change in tumor volume for different treatment groups (vehicle, ribociclib (50 mg / kg), Compound 1 (1 mg / kg, 3 mg / kg), Compound 1 + ribociclib (1 mg / kg + 50 mg / kg, respectively) and Compound 1 + ribociclib (3 mg / kg + 50 mg / kg), respectively) in a mouse xenograft LCLC-97TM1 NSCLC model over the course of treatment. FIG. 3B is a plot illustrating the percent change in body weight over time for mice in the different treatment groups. FIG. 3C is a is a plot illustrating the change in tumor volume in individual animals on day 32 (scatter plot) within each of the treatment groups. FIG. 3D is a bar graph illustrating percentage change in tumor volume on day 32 from baseline for individual animals in each treatment group.

[0013] FIGs. 4A-4B: FIG. 4A is a plot illustrating the change in tumor volume for different treatment groups (vehicle, Compound 1, 1 mg / kg and 3 mg / kg) in a mouse xenograft OVCAR3 ovarian cancer model over the treatment duration. FIG.4B is a plot illustrating the percent change in body weight over time for mice in each of the treatment groups.Page 4 of 6913238167vlAttorney Docket No. 2012034-0398

[0014] FIGs. 5A-5B: FIG. 5A is a plot illustrating the change in tumor volume for various treatment groups (vehicle, Compound 1, 0.5 mg / kg and 1 mg / kg) in a mouse xenograft OVCAR3 ovarian cancer model over the treatment duration (alternate doses explored). FIG. 5B is a plot illustrating the percent change in body weight over time for mice in each of the treatment groups.

[0015] FIGs. 6A-6C: FIG. 6A is a plot illustrating the change in tumor volume for various treatment groups (vehicle. Compound 1, 1 mg / kg, 3 mg / kg; docetaxel at 10 mg / kg; and Compound 1 (1 mg / kg and 3 mg / kg) and docetaxel (10 mg / kg) in combination) in a 22Rvl cell line derived xenograft AR+ prostate cancer model over the course of treatment duration. FIG. 6B is a scatter plot illustrating the change in tumor volume for each of the treatment groups. FIG. 6C is a waterfall plot illustrating percentage change in tumor volume on day 32 from baseline. The data indicates that Compound 1 inhibits tumor growth in a dose dependent manner in a 22Rvl CDX prostate cancer model and further that a combination of Compound 1 with the standard of care agent, docetaxel, results in enhanced anti-tumor activity.

[0016] FIGs. 7A-7B: FIG. 7A illustrates mean tumor volume versus day of dosing of Compounds 1, 4, and 5 at dosages of 0.1 mg / kg, 0.3 mg / kg and 1 mg / kg in aZR-75-1 breast cancer mouse xenograft model. FIG.7B is a scatter plot of tumor volume at day 25.

[0017] FIGs.8A-8B: FIG.8A is a plot showing percent inhibition of T47D cell proliferation by Compound 1 alone, palazestrant alone (at 1 nM and 10 nM,), and for the combination. FIG.8B is a plot showing percent inhibition of T47D cell proliferation by Compound 1 alone, palbociclib alone (at 16 nM, 63 nM, and 250 nM), and for the combination.

[0018] FIGs. 9A-9B are plots showing synergy scores determined for the combination of Compound 1 and palazestrant (FIG.9A) and Compound 1 and palbociclib (FIG. 9B).

[0019] FIGs. 10A-10C are dose response curves of percent inhibition of T47D cell proliferation for various test articles, including combinations. FIG. 10A is a dose response curve for Compound 1 alone, fulvestrant alone at varying concentrations (0.1 nM, 1.0 nM, and 3.17 nM), and Compound 1 in combination with different concentrations of fulvestrant. FIG. 10B is a dose response curve for Compound 1 alone, palazestrant alone at varying concentrations (0.1 nM, 1.0 nM, and 3.17 nM), and Compound 1 in combination with different concentrations of palazestrant.FIG. 10C is a dose response curve for Compound 1 alone, ribociclib alone at varying concentrations (16 nM, 63 nM, and 250 nM), and Compound 1 in combination with different concentrations of ribociclib.Page 5 of 6913238167vlAttorney Docket No. 2012034-0398

[0020] FIGs. 11A-11C are synergy plots for doublet combinations as described above for FIGs. 10A-10C. FIG. 11A is a synergy plot for the combination of Compound 1 and fulvestrant.FIG. 11B is a synergy plot for the combination of Compound 1 and palazestrant. FIG. 11C is a synergy plot for the combination of Compound 1 and ribociclib.

[0021] FIGs. 12A-12B are dose response curves for inhibition of T47D cell proliferation with triplet combinations of Compound 1 with fulvestrant (1 nM) and ribociclib (100 nM) (FIG. 12A), and Compound 1 with palezestrant (1 nM) and ribociclib (100 nM) (FIG. 12B).

[0022] FIGs. 13A-13C are plots illustrating tumor growth inhibition (TGI) by combinations of a KAT6 inhibitor compound with an anti-estrogen and / or a CDK.4 / 6 inhibitor in a KAT6-o verexpressing ESR1WTER+ / HER2- breast cancer cell line derived xenograft (CDX) model, T47D. FIG. 13A is a scatter plot of tumor volume (mm2) at day 33 of treatment for the various treatment groups including monotherapy, doublet combinations and triplet combinations. FIG.13B is a plot of tumor volume over time for both single agent therapies and combination therapies;FIG. 13C is a waterfall plot for monotherapies and combination therapies.

[0023] FIGs.14A-14C are plots of tumor growth inhibition (TGI) by combinations of a KAT6 inhibitor with an anti-estrogen and / or a CDK4 / 6 inhibitor in a KAT6-expressing ESR1WTER+ / HER2+ patient-derived xenograft (PDX) model, ST340. FIG. 14A is a scatter plot of tumor volume (mm2) at day 28 of treatment for the various treatment groups including monotherapy, doublet combinations and triplet combinations. FIG. 14B provides plots of tumor volume over time for both single agent therapies and combination therapies; FIG. 14C is a waterfall plot illustrating percent change in tumor volume for monotherapies and combination therapies.

[0024] FIGs. 15A-15B are plots indicating percent relative cell proliferation of the ovarian cancer cell line, UWB1.289 (BRCA1-null and +BRCA1) upon treatment with the PARP inhibitor, olaparib (FIG. 15A) or Compound 1 (FIG. 15B). Olaparib activity is known to be dependent upon BRCA status (as shown); in contrast, activity of Compound 1 was found to be independent of BRCA status.

[0025] FIGs. 16A-16B are plots of percent relative cell proliferation of the ovarian cancer cell lines, PEO1 and PEO4, versus concentration of test compound, upon treatment with platinum therapy (FIG. 16A, reporting carboplatin) or a KAT6 inhibitor (FIG. 16B, reporting Compound 1), respectively. FIG. 16B illustrates a potent antiproliferative effect of Compound 1 on platinum-resistant PEO4 ovarian cancer cells harboring a BRCA2 reversion mutation.Page 6 of 6913238167vlAttorney Docket No. 2012034-0398

[0026] FIGs. 17A-17C are synergy plots for doublet combinations of Compound 1 and each of carboplatin (FIG. 17A), olaparib (FIG. 17B), and palazestrant (FIG. 17C), respectively. The synergy analysis indicates that Compound 1 acts synergistically when combined with platinum therapy or with a PARP inhibitor in platinum-resistant sensitive PEO1 cells.DETAILED DESCRIPTION

[0027] Lysine acetyl transferases (KATs) 6 A and 6B have emerged as useful targets in the treatment of certain diseases, disorders, and conditions, such as cancer. The present disclosure encompasses the surprising discovery that Compound 1, 5-((lH-pyrazol-l-yl)methyl)-6-methoxy-N-((2,4,6-trimethoxyphenyl)sulfonyl)picolinamide:Compound 1

[0028] or a pharmaceutically acceptable salt thereof, selectively inhibits KAT6A and KAT6B relative to other KATs, making it a particularly useful therapy for the treatment of certain diseases, disorders, and conditions, such as for example, solid cancers. The KAT6A gene is either amplified or overexpressed in many breast cancer types, and ER+ / HER2- breast cancer patients were found to have poor clinical outcomes if their tumors had KAT6 overexpression. Yu, L., et al., Oncogene, 2017, 36, 2910-2918. KAT 6A and 6B overexpression has also been associated with worse clinical outcomes in other cancer types. Liu, et al., Int J. Clin Exp Pathol. 2019; 12(2): 431-442. Thus, a compound that selectively inhibits both KAT6A and KAT6B, such as, for example, Compound 1, can be particularly advantageous in treating cancer, because it acts as a single compound to inhibit both enzymatic targets.

[0029] Compound 1 was found to possess superior activity in the inhibition of the proliferation of cancer cells, and demonstrates enhanced tumor growth inhibition relative to other small molecule KAT6 inhibitor compounds in cancer xenograft models. Such a finding is unexpected based on in-vitro assay results. The illustrative data shown in the accompanying examples, in addition to favorable pharmacokinetic data for Compound 1 (e.g., higher exposure levels), among other things, contributes to the unexpected finding that Compound 1 is particularly effective in Page 7 of 6913238167vlAttorney Docket No. 2012034-0398treating diseases, disorders and conditions mediated by KAT6A and KAT6B. KAT6A and KAT6B are functionally redundant, such that inhibition of one enzymatic pathway can compensate for the other if one pathway is impaired. Inhibition of both KAT6A and KAT6B precludes this compensatory mechanism potentially leading to a more robust shutdown of disease-driving pathways dependent upon KAT6 enzymes.

[0030] Compound 1 is shown herein to possess a notable anti-proliferative effect useful for treatment of a number of different cancers or conditions, both as a monotherapy and in combination therapy, as supported by both in-vitro and in-vivo studies. As provided herein, Compound 1 is particularly effective in inhibiting cell proliferation of prostate cancer, ovarian cancer, and nonsmall cell lung cancer, as well as breast cancer, as illustrated in the examples provided in the present disclosure. Compound 1 demonstrates significant anti-tumor activity in prostate, ovarian and lung cancer (e.g., non-small cell lung cancer), as shown in exemplary xenograft studies, and exhibits synergistic activity when combined with one or more further active agents.

[0031] The present disclosure further encompasses the surprising discovery that Compound 1 shows synergistic cellular antiproliferative efficacy when combined with certain therapeutic agents, such as anti-estrogens and / or with cyclin-dependent kinase (CDK)4 / 6 inhibitors.

[0032] Additionally, the present disclosure demonstrates that treatment with Compound 1 results in tumor growth inhibition and tumor regression, depending upon dose, in certain illustrative preclinical in-vivo models. For example, as shown herein. Compound 1 shows synergistic anti-tumor efficacy in treating breast cancer, when combined with one or more further active agents, e.g., an anti-estrogenic compound and / or with a CDK4 / 6 inhibitor. For instance, in exemplary in-vivo xenograft models, treatment with Compound 1 results in enhanced tumor growth inhibition in both double and triple combinations when compared to monotherapy.

[0033] Compound 1 additionally potently inhibits proliferation of high grade serous ovarian cancer. Compound 1 has additionally been discovered to have a potent antiproliferative effect on platinum-resistant cancer cells, e.g,. platinum-resistant ovarian cancer cells. Moreover, Compound 1 acts synergistically, that is, is notably effective, when used in combination with platinum-therapy or a PARP inhibitor, in treating platinum-sensitive cancers, such as, e.g., platinum-sensitive ovarian cancer.Page 8 of 6913238167vlAttorney Docket No. 2012034-0398

[0034] These and other surprising features related to Compound 1, or a pharmaceutically acceptable salt form thereof, including related methods, such as, for example, methods of treatment, or uses thereof, will become apparent when viewed in light of the instant disclosure.Definitions

[0035] As used herein, the singular forms “a”, “an”, and “the” include plural referents unless the context clearly dictates otherwise.

[0036] About or approximately: As used herein, the term "approximately" or "about," as applied to one or more values of interest, refers to a value that is similar to a stated reference value. In general, those skilled in the art, familiar within the context, will appreciate the relevant degree of variance encompassed by "about" or "approximately" in that context. For example, in some embodiments, the term "approximately" or "about" may encompass a range of values that are within (i.e., ±) 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%. 5%, 4%, 3%, 2%, 1%, or less of the referred value.

[0037] Administering: As used herein, the term "administering" or "administration" typically refers to the administration of a composition to a subject to achieve delivery of an agent that is, or is included in, a composition to a target site or a site to be treated. Those of ordinary skill in the art will be aware of a variety of routes that may, in appropriate circumstances, be utilized for administration to a subject, for example a human. For example, in some embodiments, administration may be ocular, oral, parenteral, topical, etc. In some particular embodiments, administration may be bronchial (e.g., by bronchial instillation), buccal, dermal (which may be or comprise, for example, one or more of topical to the dermis, intradermal, interdermal. transdermal, etc.), enteral, intra-arterial, intradermal, intragastric, intramedullary, intramuscular, intranasal, intraperitoneal, intrathecal, intravenous, intraventricular, within a specific organ (e.g., intrahepatic). mucosal, nasal, oral, rectal, subcutaneous, sublingual, topical, tracheal (e.g., by intratracheal instillation), vaginal, vitreal, etc. In some embodiments, administration may be parenteral. In some embodiments, administration may be oral. In some particular embodiments, administration may be intravenous. In some particular embodiments, administration may be subcutaneous. In some embodiments, administration may involve only a single dose. In some embodiments, administration may involve application of a fixed number of doses. In some embodiments, administration may involve dosing that is intermittent (e.g., a plurality of dosesPage 9 of 6913238167vlAttorney Docket No. 2012034-0398separated in time) and / or periodic (e.g., individual doses separated by a common period of time) dosing. In some embodiments, administration may involve continuous dosing (e.g., perfusion) for at least a selected period of time.

[0038] Agent: As used herein, the term “agent”, refers to an entity, for example, a compound or molecule of any chemical class, such as a small molecule, polypeptide, nucleic acid, saccharide, naturally-occurring or non-naturally occurring polymer, lipid, metal, etc., or complex combination, mixture, or system thereof. In some embodiments, the term “agent” also encompasses a compound, molecule, or entity that comprises a polymer. In some embodiments, the term may refer to a compound or entity that comprises one or more polymeric moieties. In some embodiments, the term “agent” may refer to a compound, molecule, or entity that is substantially free of a particular polymer or polymeric moiety. In some embodiments, the term may refer to a compound, molecule, or entity that lacks or is substantially free of any polymer or polymeric moiety.

[0039] Small molecule: As used herein, the term “small molecule” means a low molecular weight organic and / or inorganic compound. As used herein, a “small molecule”, e.g., an organic molecule, is a molecule having a mass that is less than about 1 kilodaltons (kD) or a molar mass that is less than about 1000 g / mol. For example, a small molecule can have a mass that is less than about 800 daltons (D), or less than about 600 D, or is less than about 500 D. As used herein, a mass of a compound in daltons is considered to be numerically equal to its mass in grams per mole.

[0040] Biological sample: As used herein, the term “biological sample” typically refers to a sample obtained or derived from a biological source (e.g., a tissue or organism or cell culture) of interest, as described herein. In some embodiments, a source of interest comprises an organism, such as an animal or human. In some embodiments, a biological sample is or comprises biological tissue or fluid. In some embodiments, a biological sample may be or comprise bone marrow; blood; blood cells; ascites; tissue or fine needle biopsy samples: cell-containing body fluids; free floating nucleic acids; sputum; saliva; urine; cerebrospinal fluid, peritoneal fluid; pleural fluid; feces; lymph; gynecological fluids; skin swabs; vaginal swabs; oral swabs; nasal swabs; washings or lavages such as a ductal lavages or broncheoalveolar lavages; aspirates; scrapings; bone marrow specimens; tissue biopsy specimens; surgical specimens; feces, other body fluids, secretions, and / or excretions; and / or cells therefrom, etc. In some embodiments, a biological sample is or comprises cells obtained from an individual. In some embodiments, obtained cells are or include Page 10 of 6913238167vlAttorney Docket No. 2012034-0398cells from an individual from whom the sample is obtained. In some embodiments, a sample is a “primary sample” obtained directly from a source of interest by any appropriate means. For example, in some embodiments, a primary biological sample is obtained by methods selected from the group consisting of biopsy (e.g., fine needle aspiration or tissue biopsy), surgery, collection of body fluid (e.g., blood, lymph, feces etc.), etc. In some embodiments, as will be clear from context, the term “sample” refers to a preparation that is obtained by processing (e.g.. by removing one or more components of and / or by adding one or more agents to) a primary sample. For example, filtering using a semi-permeable membrane. Such a “processed sample” may comprise, for example, nucleic acids or proteins extracted from a sample or obtained by subjecting a primary sample to techniques such as amplification or reverse transcription of mRNA, isolation and / or purification of certain components, etc.

[0041] Carrier: As used herein, the term “carrier” refers to a diluent, adjuvant, excipient, or vehicle with which a composition or agent is administered. In some exemplary embodiments, carriers can include sterile liquids, such as, for example, water and oils, including oils of petroleum, animal, vegetable or synthetic origin, such as, for example, peanut oil, soybean oil, mineral oil, sesame oil and the like. In some embodiments, carriers are or include one or more solid components.

[0042] Combination therapy: As used herein, the term “combination therapy” refers to those situations in which a subject is simultaneously exposed to two or more therapeutic regimens (e.g., two or more therapeutic agents or modality (ies)). In some embodiments, the two or more regimens may be administered simultaneously; in some embodiments, such regimens may be administered sequentially (e.g., all “doses” of a first regimen are administered prior to administration of any doses of a second regimen); in some embodiments, such agents are administered in overlapping dosing regimens. In some embodiments, “administration” of combination therapy may involve administration of one or more agent(s) or modality(ies) to a subject receiving the other agent(s) or modality(ies) in the combination. For clarity, combination therapy does not require that individual agents be administered together in a single composition (or even necessarily at the same time), although in some embodiments, two or more agents, or active moieties thereof, may be administered together in a combination composition, or even in a combination compound (e.g., as part of a single chemical complex or covalent entity).Page 11 of 6913238167vlAttorney Docket No. 2012034-0398

[0043] Comparable'. As used herein, the term “comparable” refers to two or more agents, entities, situations, sets of conditions, etc., that may not be identical to one another but that are sufficiently similar to permit comparison therebetween so that one skilled in the art will appreciate that conclusions may reasonably be drawn based on differences or similarities observed. In some embodiments, comparable sets of conditions, circumstances, individuals, or populations are characterized by a plurality of substantially identical features and one or a small number of varied features. Those of ordinary skill in the art will understand, in context, what degree of identity is required in any given circumstance for two or more such agents, entities, situations, sets of conditions, etc. to be considered comparable. For example, those of ordinary skill in the art will appreciate that sets of circumstances, individuals, or populations are comparable to one another when characterized by a sufficient number and type of substantially identical features to warrant a reasonable conclusion that differences in results obtained or phenomena observed under or with different sets of circumstances, individuals, or populations are caused by or indicative of the variation in those features that are varied.

[0044] Composition: Those skilled in the art will appreciate that the term “composition” is used to refer to a discrete physical entity that comprises one or more specified components. In general, unless otherwise specified, a composition may be of any form - e.g., gas, gel, liquid, solid, etc.

[0045] Dosage form or unit dosage form: Those skilled in the art will appreciate that the term “dosage form” may be used to refer to a physically discrete unit of an active agent (e.g., a therapeutic or diagnostic agent) for administration to a subject. Typically, each such unit contains a predetermined quantity of active agent. In some embodiments, such quantity is a unit dosage amount (or a whole fraction thereof) appropriate for administration in accordance with a dosing regimen that has been determined to correlate with a desired or beneficial outcome when administered to a relevant population (i.e.. with a therapeutic dosing regimen).

[0046] Dosing regimen or therapeutic regimen: Those skilled in the art will appreciate that the terms “dosing regimen” and “therapeutic regimen” may be used to refer to a set of unit doses (typically more than one) that are administered individually to a subject, typically separated by periods of time. In some embodiments, a given therapeutic agent has a recommended dosing regimen, which may involve one or more doses. In some embodiments, a dosing regimen comprises a plurality of doses each of which is separated in time from other doses. In some Page 12 of 6913238167vlAttorney Docket No. 2012034-0398embodiments, individual doses are separated from one another by a time period of the same length; in some embodiments, a dosing regimen comprises a plurality of doses and at least two different time periods separating individual doses. In some embodiments, all doses within a dosing regimen are of the same unit dose amount. In some embodiments, different doses within a dosing regimen are of different amounts. In some embodiments, a dosing regimen comprises a first dose in a first dose amount, followed by one or more additional doses in a second dose amount different from the first dose amount. In some embodiments, a dosing regimen comprises a first dose in a first dose amount, followed by one or more additional doses in a second dose amount same as the first dose amount. In some embodiments, a dosing regimen is correlated with a desired or beneficial outcome when administered across a relevant population (i.e., is a therapeutic dosing regimen).

[0047] Effective Amount. The term “effective amount” refers to the amount of a compound or agent sufficient to effect beneficial or desired results (e.g., a therapeutic, ameliorative, inhibitory, or preventative result). An effective amount can be administered in one or more administrations, applications, or dosages and is not intended to be limited to a particular formulation or administration route.

[0048] Excipient: As used herein, the term “excipient” refers to a non-therapeutic agent that may be included in a pharmaceutical composition, for example, to provide or contribute to a desired consistency or stabilizing effect. Suitable pharmaceutical excipients include, for example, starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like. Illustrative pharmaceutically acceptable excipients suitable for use in a pharmaceutical composition can be found, e.g., in, “The Handbook of Pharmaceutical Excipients”, 9thed., Sheskey, P. J., et al., Pharmaceutical Press, 2020.

[0049] Inhibitor: As used herein, the term “inhibitor” refers to an agent, e.g., a compound that binds to or inhibits a target with a measurable affinity. For example, in some embodiments, an inhibitor has an IC50 and / or binding constant of less than about 50 μM, less than about 1 μM, less than about 500 nM, less than about 100 nM, less than about 10 nM, or less than about 1 nM. In some embodiments, an inhibitor is an agent whose presence or level correlates with decreased level or activity of a target, as compared with that observed absent the agent (or with the agent at a different level). In some embodiments, an inhibitor may be a direct inhibitor in that it exerts its influence directly on (e.g., interacts directly with) the target; in some embodiments, an inhibitor Page 13 of 6913238167vlAttorney Docket No. 2012034-0398may be an indirect inhibitor in that it exerts its influence indirectly (e.g., by acting on, such as interacting with, a regulator of the target, or with some other component or entity).

[0050] Oral: The phrases “oral administration” and “administered orally” as used herein have their art-understood meaning referring to administration by mouth of a compound or composition.

[0051] Patient or subject: As used herein, the term “patient” or “subject” refers to any organism to which a provided composition is or may be administered, e.g.. for experimental, diagnostic, prophylactic, cosmetic, and / or therapeutic purposes. Typical patients or subjects include animals (e.g., mammals such as mice, rats, rabbits, non-human primates, and / or humans). In some embodiments, a patient is a human. In some embodiments, a patient or a subject is suffering from or susceptible to one or more disorders or conditions. In some embodiments, a patient or subject displays one or more symptoms of a disorder or condition. In some embodiments, a patient or subject has been diagnosed with one or more disorders or conditions. In some embodiments, a patient or a subject is receiving or has received certain therapy to diagnose and / or to treat a disease, disorder, or condition.

[0052] Pharmaceutical composition: As used herein, the term “pharmaceutical composition” refers to an active agent, formulated together with one or more pharmaceutically acceptable carriers or excipients. In some embodiments, the active agent is present in unit dose amount appropriate for administration in a therapeutic or dosing regimen that shows a statistically significant probability of achieving a predetermined therapeutic effect when administered to a relevant population. In some embodiments, pharmaceutical compositions may be specially formulated for administration in solid or liquid form, including those adapted for the following: oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue; parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation; topical application, for example, as a cream, ointment, or a controlled-release patch or spray applied to the skin, lungs, or oral cavity; intravaginally or intrarectally, for example, as a pessary, cream, or foam; sublingually; ocularly; transdermally; or nasally, pulmonary, and to other mucosal surfaces.

[0053] Pharmaceutically acceptable: As used herein, the phrase “pharmaceutically acceptable” refers to those compounds, materials, compositions, and / or dosage forms which are,Page 14 of 6913238167vlAttorney Docket No. 2012034-0398within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0054] Pharmaceutically acceptable salt: The term “pharmaceutically acceptable salt”, as used herein, refers to salts of such compounds that are appropriate for use in pharmaceutical contexts, i.e., salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of 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. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977). Exemplary pharmaceutically acceptable salts include, but are not limited to, non-toxic acid addition salts, which are 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.

[0055] Acids which are generally considered suitable for the formation of pharmaceutically useful salts from basic pharmaceutical compounds are discussed, for example, by P. Stahl et al., Camille G. (eds.) Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley-VCH; S. Berge el al., Journal of Pharmaceutical Sciences 1977, 66(1), 1-19; P. Gould, International J. of Pharmaceutics 1986, 33, 201-217; Anderson et al., The Practice of Medicinal Chemistry (1996), Academic Press, New York; and in The Orange Book (Food & Drug Administration, Washington, D. C. on their website). These disclosures are incorporated herein by reference.Page 15 of 6913238167vlAttorney Docket No. 2012034-0398

[0056] Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(C1–4alkyl)4salts. 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.

[0057] Prevent or prevention: As used herein, the terms “prevent” or “prevention”, when used in connection with the occurrence of a disease, disorder, and / or condition, refer to reducing the risk of developing the disease, disorder and / or condition and / or to delaying onset of one or more characteristics or symptoms of the disease, disorder or condition. Prevention may be considered complete when onset of a disease, disorder or condition has been delayed for a predefined period of time.

[0058] Reference: As used herein describes a standard or control relative to which a comparison is performed. For example, in some embodiments, an agent, animal, individual, population, sample, sequence or value of interest is compared with a reference or control agent, animal, individual, population, sample, sequence or value. In some embodiments, a reference or control is tested and / or determined substantially simultaneously with the testing or determination of interest. In some embodiments, a reference or control is a historical reference or control, optionally embodied in a tangible medium. Typically, as would be understood by those skilled in the art, a reference or control is determined or characterized under comparable conditions or circumstances to those under assessment. Those skilled in the art will appreciate when sufficient similarities are present to justify reliance on and / or comparison to a particular possible reference or control.

[0059] Suffering from: An individual who is “suffering from” a disease, disorder, and / or condition has been diagnosed with and / or displays one or more symptoms of a disease, disorder, and / or condition.

[0060] Treat: As used herein, the terms “treat,” “treatment,” or “treating” refer to any method used to partially or completely alleviate, ameliorate, relieve, inhibit, prevent, delay onset of, reduce severity of, and / or reduce incidence of one or more symptoms or features of a disease, disorder, and / or condition. Treatment may be administered to a subject who does not exhibit signs of a disease, disorder, and / or condition. In some embodiments, treatment may be administered to a Page 16 of 6913238167vlAttorney Docket No. 2012034-0398subject who exhibits only early signs of the disease, disorder, and / or condition, for example, for the purpose of decreasing the risk of developing pathology associated with the disease, disorder, and / or condition.Compound 1

[0061] The present disclosure encompasses an insight, among other things, that Compound 1Compound 1or a pharmaceutically acceptable salt thereof, is useful in treating diseases, disorders, and conditions by inhibiting both K. AT6A and K. AT6B, and has demonstrated efficacy in both in vitro and in vivo models in treating certain cancers, such as ovarian, prostate, and non-small cell lung cancer (“NSCLC”).

[0062] Compound 1, also known as 5-((lH-pyrazol-l-yl)methyl)-6-methoxy-N-((2,4,6-trimethoxyphenyl)sulfonyl)picolinamide, is described in PCT Application Publication No. WO2024 / 189598 (which is incorporated herein by reference in its entirety) as Compound No. 224, and in Example 10. The inhibitory activity of Compound 1 against KAT6A is described in Example 30 of WO2024 / 189598.

[0063] The present disclosure encompasses the surprising discovery that Compound 1 useful as a highly selective inhibitor of KAT6A and KAT6B. The selective nature of Compound 1 affords new therapeutic uses for treating new diseases, disorders, and conditions, as described in the present application. Compound 1 has been found to be extremely effective in potently inhibiting proliferation of certain cancer types, in addition to exhibiting notable efficacy in inhibiting or regressing tumor growth, both as a mono-therapy and in combination with one or more additional active agents.

[0064] As described herein, reference to “Compound 1” is intended to include reference pharmaceutically acceptable salts thereof, unless otherwise specified. In some embodiments, Compound 1 is in the form of a pharmaceutically acceptable salt (e.g., a pharmaceuticallyPage 17 of 6913238167vlAttorney Docket No. 2012034-0398acceptable salt of Compound 1). In some embodiments, Compound 1 is in free base form (e.g., a free base form of Compound 1).Uses, Formulation, and AdministrationKAT6A / KAT6B

[0065] KAT6 proteins belong to the MYST family of acetyltransferases, which includes MOZ, Ybf2 / Sas3, Sas2, and Tip60, of which there are five members of the KAT family: KAT5, KAT6A (formerly known as both MOZ and MYST3), KAT6B (formerly known as both MORF and MYST4), KAT7 and KAT8. Wiesel-Motiuk & Assaraf, Drug Resistance Updates, 53, 100729 (Dec. 2020). The members of this family share a highly conserved MYST domain consisting of an Acetyl-CoA-binding motif and a PHD (plant homeodomain)-type zinc finger domain. KAT6 proteins play a key role in regulation of gene expression via modification of histone lysine residues that modulate chromatin organization. KAT6A and KAT6B interact with the bromodomain-PHD finger protein (BRPF1 / 2 / 3) through their MYST domain. KAT6A and KAT6B can be responsible for the formation of malignancies such as liver, breast, urogenital, gastrointestinal tract, endometrium and lung tumors. Indeed, it has been shown that KAT6A and KAT6B proteins stimulate cancer cell growth by influencing the cell cycle. For this reason, inhibiting their action can stop malignancy and put it into a completely dormant state without destroying its cells. Olbromski, et al., Nature Scientific Reports (2024) 14:26935.

[0066] The present disclosure encompasses the surprising discovery that Compound 1, or a pharmaceutically acceptable salt thereof, is useful in the treatment of diseases, disorders, or conditions associated with KAT6A and / or KAT6B. In some embodiments, the present disclosure provides a method of inhibiting KAT6A and KAT6B in a patient in need thereof, comprising administering to a subject in need thereof an effective amount of Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a method of inhibiting KAT6B comprising administering to a subject in need thereof an effective amount of Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, a disease, disorder, or condition associated with KAT6A and KAT6B is a cancer. In some embodiments, a disease, disorder, or condition associated with KAT6B is a cancer. In some embodiments, a cancer is an advanced or metastatic cancer. As used herein, advanced cancer Page 18 of 6913238167vlAttorney Docket No. 2012034-0398refers to a cancer that has spread beyond its site of origin to surrounding local tissues (e.g., is locally advanced). As used herein, metastatic cancer refers to cancer that has spread from beyond its site of origin to distant tissues or organs, including, for example, the bones, lungs, liver, or brain.

[0067] In some embodiments, the cancer is selected from brain gliomas, glioblastomas, astrocytomas, glioblastoma multiforme (GBM), Bannayan-Zonana syndrome, Cowden disease, Lhermitte-Duclos disease, breast cancer, colon cancer, head and neck cancer, kidney, liver, lung cancer, bone cancer, colorectal cancer, germ cell cancer, melanoma, ovarian cancer, pancreatic cancer, adenocarcinoma, ductal adenocarcinoma, adenosquamous carcinoma, acinar cell carcinoma, glucagonoma, insulinoma, prostate, sarcoma and thyroid cancer, lymphoblastic T cell leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, hairy-cell leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia, chronic neutrophilic leukemia, acute lymphoblastic T cell leukemia, plasmacytoma, immunoblastic large cell leukemia, mantle cell leukemia, megakaryoblastic leukemia, multiple myeloma, acute megakaryocytic leukemia, promyelocytic leukemia, erythroleukemia, malignant lymphoma, Hodgkin’s lymphoma, nonHodgkin’s lymphoma, lymphoblastic T cell lymphoma, Burkitt’s lymphoma, follicular lymphoma, neuroblastoma, bladder cancer, urothelial cancer, vulval cancer, uterine cancer, cervical cancer, endometrial cancer, renal cancer, mesothelioma, esophageal cancer, salivary gland cancer, hepatocellular cancer, gastric cancer, nasopharyngeal cancer, buccal cancer, cancer of the mouth, gastrointestinal stromal tumor (GIST), neuroendocrine cancers, testicular cancer, virus-related cancer, and non-small cell lung cancer (“NSCLC”). In some embodiments, a cancer is ovarian cancer, prostate cancer, or non-small cell lung cancer (“NSCLC”).

[0068] In some embodiments, a cancer is a breast cancer. In some embodiments, a breast cancer is a triple negative breast cancer. In some embodiments, a breast cancer is ER+ / HER2+ breast cancer. In some embodiments, a breast cancer is ER- / HER2+ breast cancer. In some embodiments, a breast cancer is ER+ / HER2+ advanced or metastatic breast cancer. In some embodiments, a breast cancer is an ESRI mutant breast cancer. In some embodiments, a breast cancer is ESRlwt (ESRI wild type) ER+ / HER2+ breast cancer. In some embodiments, a breast cancer is ER+ / HER2- advanced or metastatic breast cancer. In some embodiments, the cancer is a breast cancer, wherein the disease, disorder, or condition is breast cancer, optionally wherein: the breast cancer is ER- / HER2+ breast cancer; the breast cancer is triple negative breast cancer;Page 19 of 6913238167vlAttorney Docket No. 2012034-0398the breast cancer is advanced or metastatic breast cancer; the breast cancer is ER+ / HER2+ breast cancer; the breast cancer is ESRlwt ER+ / HER2+ breast cancer; or the breast cancer is an ESRI mutant breast cancer.

[0069] In some embodiments, a cancer is an ovarian cancer. In some embodiments, an ovarian cancer is a platinum-resistant ovarian cancer. In some embodiments, an ovarian cancer is high grade serous ovarian cancer. In some embodiments, an ovarian cancer is platinum-resistant high grade serous ovarian cancer. In some embodiments, a subject suffering from ovarian cancer has a BRCA mutation. In some embodiments, a subject suffering from ovarian cancer does not have a BRCA mutation. In some embodiments, an ovarian cancer is advanced or metastatic ovarian cancer.

[0070] In some embodiments, a cancer is a prostate cancer. In some embodiments, a prostate cancer is castration-resistant prostate cancer. In some embodiments, a prostate cancer is advanced or metastatic prostate cancer. In some embodiments, a prostate cancer is castration-resistant prostate cancer advanced or metastatic prostate cancer.

[0071] In some embodiments, a cancer is non-small cell lung cancer.

[0072] In some embodiments, a subject has a tumor derived from a cancer described herein. That is, in some embodiments, a subject has a cancer, as described herein, and wherein the cancer has caused the subject to grow a tumor that is associated with (or derived from) said cancer.

[0073] In some embodiments, the present disclosure provides a method of inhibiting tumor growth, wherein the tumor is associated with ovarian cancer, prostate cancer, or non-small-cell lung cancer, the method comprising administering to a subject in need thereof an effective amount of Compound 1I X A H1T X, AzN\z° _NCompound 1or a pharmaceutically acceptable salt thereof.

[0074] In some embodiments, the present disclosure provides a method of inhibiting tumor growth, wherein the tumor is associated with breast cancer, the method comprising administering to a subject in need thereof an effective amount of Compound 1Page 20 of 6913238167vlAttorney Docket No. 2012034-0398IQ,p n I-6’ wCompound 1or a pharmaceutically acceptable salt thereof.

[0075] In some embodiments, the present disclosure provides a method of inhibiting KAT6A and / or KAT6B in a biological sample comprising contacting the biological sample with Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a method of inhibiting KAT6A and KAT6B in a biological sample comprising contacting the biological sample with Compound 1, or a pharmaceu tic ally acceptable salt thereof. In some embodiments, the present disclosure provides a method of inhibiting KAT6B in a biological sample comprising contacting the biological sample with Compound 1, or a pharmaceutically acceptable salt thereof.

[0076] In some embodiments, the present disclosure provides a method of treating a disease, disorder, or condition associated with KAT6A and / or KAT6B comprising administering Compound 1 (i.e., a first agent that is Compound 1) and a second therapeutic agent. In some embodiments, a second therapeutic agent is a selective estrogen receptor modulator (SERM), a selective estrogen receptor degrader (SERD), a CDK4 / 6 inhibitor, a CDK4-selective inhibitor, a PI3 kinase inhibitor, an aromatase inhibitor, an mTOR inhibitor, an antibody to or inhibitor of PD-1, PD-L1 or CTLA-4, antibody to or inhibitor of EGFR, PDGFR, or IGFR, a USP1 inhibitor, an AKT inhibitor, a PARP inhibitor, a taxoid agent, or an antineoplastic agent.

[0077] In some embodiments, a second therapeutic agent is a Selective Estrogen Receptor Modulator (SERM). In some embodiments, the SERM is tamoxifen, endoxifene, raloxifene, toremifene, lasofoxifene, ospemifene, elacestrant or bazedoxifene.

[0078] In some embodiments, a second therapeutic agent is a Selective Estrogen Receptor Degrader. In some embodiments, the SERD is fulvestrant, camizestrant, palazestrant, imlunestrant, elacestrant, or giredestrant.

[0079] In some embodiments, a second therapeutic agent is a CDK4 / 6 inhibitor. In some embodiments, a CDK4 / 6 inhibitor is selected from palbociclib, abemaciclib, ribociclib, lerociclib, trilaciclib, and SHR6390. In some embodiments, a CDK4 / 6 inhibitor is selected from ribociclib, palbociclib, and abemaciclib.Page 21 of 6913238167vlAttorney Docket No. 2012034-0398

[0080] In some embodiments, a second therapeutic agent is an mTOR inhibitor. In some embodiments, an mTOR inhibitor is selected from everolimus, sirolimus, temsirolimus, and LY3023414.

[0081] In some embodiments, a second therapeutic agent is a CDK4-selective inhibitor. In some embodiments, a CDK-4 selective inhibitor is PF-07220060 (atirmociclib).

[0082] In some embodiments, a second therapeutic agent is a PI3 kinase inhibitor. In some embodiments, a PI3 kinase inhibitor is selected from perifosine, CAL101, BEZ235, XL147, XL765, GDC-0941, and IPI-145.

[0083] In some embodiments, a PI3 kinase inhibitor is a PIK3CA inhibitor. In some embodiments, a PIK3CA inhibitor is selected from alpelisib, taselisib, LY3023414, Inavolisib, STX-478, RLY-2608, LOXO-783, OKI-219, and TOS-358.

[0084] In some embodiments, a second therapeutic agent is an aromatase inhibitor. In some embodiments, an aromatase inhibitor is selected from aminoglutethimide, testolactone, anastrozole, letrozole. exemestane, vorozole, formestane, fadrozole, 4-hydroxyandrostenedione, 1, 4, 6-androstatrien-3, 17-dione, and 4-androstene-3, 6, 17-trione.

[0085] In some embodiments, a second therapeutic agent is an antibody to or inhibitor of PD-1, PD-L1 or CTLA-4.

[0086] In some embodiments, a second therapeutic agent is an antibody to or inhibitor of EGFR, PDGFR, or IGFR. In some embodiments, a second therapeutic agent is erlotinib or gefitinib.

[0087] In some embodiments, a second therapeutic agent is a USP1 inhibitor.

[0088] In some embodiments, a second therapeutic agent is an AKT inhibitor. In some embodiments, an additional anti-cancer agent is capivasertib.

[0089] In some embodiments, a second therapeutic agent is PARP inhibitor. In some embodiments, a PARP inhibitor is olaparib, niraparib, or rucaparib.

[0090] In some embodiments, a second therapeutic agent is a taxoid agent. In some embodiments, a taxoid agent is paclitaxel or docetaxel.

[0091] In some embodiments, a second therapeutic agent is an antineoplastic agent. In some embodiments, an antineoplastic agent is 5-fluorouracil (5-FU), capecitabine, gemcitabine, an ATR inhibitor (e.g., camonsertib), or a platinum agent (e.g., cisplatin, carboplatin, or oxaliplatin).Page 22 of 6913238167vlAttorney Docket No. 2012034-0398

[0092] In some embodiments, a second therapeutic agent is a platinum agent. In some embodiments, a platinum agent is cisplatin, carboplatin, or oxaliplatin. In some embodiments, a platinum agent is cisplatin. In some embodiments, a platinum agent is carboplatin. In some embodiments, a platinum agent is oxaliplatin

[0093] In some embodiments, the present disclosure provides a method of treating a disease, disorder, or condition associated with KAT6A and / or KAT6B comprising administering Compound 1 (i.e., a first agent that is Compound 1), a second therapeutic agent, and a third therapeutic agent.

[0094] In some embodiments, the third therapeutic agent is a selective estrogen receptor modulator (SERM), a selective estrogen receptor degrader (SERD), a CDK4 / 6 inhibitor, a CDK4-selective inhibitor, a PI3 kinase inhibitor, an aromatase inhibitor, an mTOR inhibitor, an antibody to or inhibitor of PD- 1, PD-L1 or CTLA-4, an antibody to or inhibitor of EGFR, PDGFR, or IGFR, a USP1 inhibitor, an AKT inhibitor, a PARP inhibitor, a taxoid agent, or an antineoplastic agent.

[0095] In some embodiments, the third therapeutic agent is docetaxel. In some embodiments, the third therapeutic agent is fulvestrant. In some embodiments, the third therapeutic agent is palazestrant. In some embodiments, the third therapeutic agent is ribociclib. In some embodiments, the third therapeutic agent is palbociclib. In some embodiments, the third therapeutic agent is a platinum agent. In some embodiments, the third therapeutic agent is a PARP inhibitor.

[0096] In some embodiments, the present disclosure provides a method of treating a subject suffering from a cancer, wherein the subject has previously received an alternative anti-cancer treatment. In some embodiments, an alternative anti-cancer agent is a standard of care agent for a given cancer type. In some embodiments, an alternative anti-cancer treatment is an androgen receptor antagonist, a tyrosine kinase inhibitor, an mTOR inhibitor, or a PARP inhibitor. In some embodiments, an alternative anti-cancer treatment is an androgen receptor antagonist. In some embodiments, an alternative anti-cancer treatment is a tyrosine kinase inhibitor. In some embodiments, an alternative anti-cancer treatment is an mTOR inhibitor. In some embodiments, an alternative anti-cancer treatment is a PARP inhibitor. In some embodiments, an alternative anticancer treatment is a taxoid agent. In some embodiments, an alternative anti-cancer treatment is an antineoplastic agent. In some embodiments, the subject suffering from a cancer has previously been treated with platinum therapy. In some embodiments, the subject suffering from a cancer develops resistance to platinum therapy.Page 23 of 6913238167vlAttorney Docket No. 2012034-0398

[0097] In some embodiments, a cancer is prostate cancer or non-small cell lung cancer, and the second therapeutic agent is a taxoid agent. In some embodiments, a cancer is prostate cancer or non-small cell lung cancer, and the second therapeutic agent is docetaxel.

[0098] In some embodiments, a cancer is breast cancer, and a second a therapeutic agent is a SERD. In some embodiments, a cancer is breast cancer, and a second therapeutic agent is fulvestrant or palazestrant. In some embodiments, a cancer is breast cancer, and a second therapeutic agent is fulvestrant. In some embodiments, a cancer is breast cancer, and a second therapeutic agent is palazestrant.

[0099] In some embodiments, some embodiments, a cancer is breast cancer, a second therapeutic agent is a SERD, and a third therapeutic agent is a CDK4 / 6 inhibitor. In some embodiments, some embodiments, a cancer is breast cancer, a second therapeutic agent is fulvestrant or palazestrant, and a third therapeutic agent is ribociclib. In some embodiments, some embodiments, a cancer is breast cancer, a second therapeutic agent is fulvestrant, and a third therapeutic agent is ribociclib. In some embodiments, some embodiments, a cancer is breast cancer, a second therapeutic agent is palazestrant, and a third therapeutic agent is ribociclib.

[0100] In some embodiments, the present disclosure provides a method of treating a platinumsensitive ovarian cancer, comprising administering to a subject in need thereof an effective amount of Compound 1,Compound 1or a pharmaceutically acceptable salt thereof, and a PARP inhibitor.

[0101] In some embodiments, the present disclosure provides a method of treating a platinum- resistant ovarian cancer, comprising administering to a subject in need thereof an effective amount of Compound 1,Compound 1or a pharmaceutically acceptable salt thereof, a PARP inhibitor, and a platinum agent.Page 24 of 6913238167vlAttorney Docket No. 2012034-0398

[0102] In some embodiments, the present disclosure provides a method of treating a platinumsensitive ovarian cancer, comprising administering to a subject in need thereof an effective amount of Compound 1,Compound 1or a pharmaceutically acceptable salt thereof, a PARP inhibitor, and / or a platinum agent.

[0103] In some embodiments, the present disclosure provides a dosing regimen for treating a disease, disorder, or condition associated with KAT6A and / or KAT6B, such as a cancer. For example, as illustrated in the Examples described herein, Compound 1 has been shown to inhibit proliferation across cell lines in doses such as from 0.5 to about 3 mg / kg in a mouse model.. A person of skill in the art would understand how to determine an appropriate human dose amount in view of provided mouse dose amounts, such as by method reporting by Nair and Jacob, in J. Basic Clin. Pharm., 2016 Mar;7 (2): 27-31. A person of skill in the art would also be aware of alternative methods of converting a mouse dose (or other animal-based dose) to a human dose, such as by body surface area scaling, allometric scaling, or physiologically based pharmacokinetic (PBPK) modeling.

[0104] In some embodiments of methods described herein, Compound 1 is administered once every other day, once per day, twice per day, once per week, twice per week, or once per month. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered once per day. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered twice per day. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered once every other day. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered once per week. In some embodiments, Compound 1 is administered in an amount that is from about 0.5 mg to about 1000 mg per day. In some embodiments, Compound 1 is administered in an amount that is from about 1 mg to about 500 mg per day. In some embodiments, Compound 1 is administered in an amount that is from about 1 mg to about 150 mg per day. In some embodiments, Compound 1 is administered in an amount that is from about 1 mg to about 100 mg per day. In some embodiments, Compound 1 is administered in an amount that is from about 0.5 mg to about 1000Page 25 of 6913238167vlAttorney Docket No. 2012034-0398mg per dose. In some embodiments, Compound 1 is administered in an amount that is from about 1 mg to about 500 mg per dose. In some embodiments, Compound 1 is administered in an amount that is from about 1 mg to about 150 mg per dose. In some embodiments, Compound 1 is administered in an amount that is from about 1 mg to about 100 mg per dose. In some embodiments, Compound 1 is administered in an amount that is from about 0.5 mg to about 100 mg per dose. In some embodiments. Compound 1 is administered in an amount that is from about 0.5 mg to about 50 mg per dose. In some embodiments, Compound 1 is administered in an amount that is from about 0.5 mg to about 25 mg per dose. In some embodiments, Compound 1 is administered in an amount that is from about 0.5 mg to about 20 mg per dose. In some embodiments, Compound 1 is administered in an amount that is from about 2.5 mg to about 20 mg. In some embodiments, Compound 1 is administered in an amount that is about 0.5 mg, about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, about 10 mg, about 10.5 mg, about 11 mg, about 11.5 mg, about 12 mg, about 12.5 mg, about 13 mg, about 13.5 mg, about 14 mg, about 14.5 mg, about 15 mg, about 15.5 mg, about 16 mg, about 16.5 mg, about 17 mg, about 17.5 mg, about 18 mg, about 18.5 mg, about 19 mg, about 19.5 mg, about 20 mg, about 20.5 mg, about 21 mg, about 21.5 mg, about 22 mg, about 22.5 mg, about 23 mg, about 23.5 mg, about 24 mg, about 24.5 mg, or about 25 mg per dose. It is understood that provided dose amounts are calculated according to the corresponding free base weight.

[0105] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered orally. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered as a solid dosage form. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered as a capsule or a tablet. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered as part of a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[0106] In some embodiments, a method described herein provides tumor regression in a cancer that is from about 50% to about 150%, at baseline, as determined by the tumor growth inhibition formula. As used herein, the tumor growth inhibition formula is: TGI (%) = [1-(Ti-T0) / (Vi-V0)] ×100; where Ti is the average tumor volume of a treatment group on a given day, T0 is the average Page 26 of 6913238167vlAttorney Docket No. 2012034-0398tumor volume of the treatment group on the first day of treatment, Vi is the average tumor volume of the vehicle control group on the same day with Ti, and V0 is the average tumor volume of the vehicle group on the first day of treatment. In some embodiments, a method described herein provides tumor regression in a cancer that is from about 50% to about 150%, at baseline, as determined by the tumor growth inhibition formula, and wherein the cancer is ovarian cancer, prostate cancer, or non-small cell lung cancer.Pharmaceutically Acceptable Compositions

[0107] According to another embodiment, the present disclosure provides a pharmaceutical composition comprising Compound 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, adjuvant, or vehicle. In certain embodiments, a pharmaceutical composition described herein is formulated for administration to a patient in need of such composition. In some embodiments, a pharmaceutical composition described herein is formulated for oral administration to a patient. In some embodiments, a pharmaceutical composition is a solid dosage form. In some embodiments, a solid dosage form is in the form of a tablet or capsule. In some embodiments, a solid dosage form is in the form of a tablet. In some embodiments, a solid dosage form is in the form of a capsule.

[0108] Compounds and compositions, according to method of the present disclosure, are administered using any amount and any route of administration effective for treating or lessening the severity of a disorder provided herein. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the particular agent, its mode of administration, and the like. Compounds described herein are preferably formulated in unit dosage form for ease of administration and uniformity of dosage.

[0109] Compositions of the present disclosure may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, intraperitoneally, intracisternally or via an implanted reservoir. In some embodiments, the compositions are administered orally, intraperitoneally or intravenously.

[0110] Sterile injectable forms of the compositions described herein may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known inPage 27 of 6913238167vlAttorney Docket No. 2012034-0398the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium.

[0111] For this purpose, any bland fixed oil may be employed including synthetic mono- or di-glycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.

[0112] Injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0113] In order to prolong the effect of a compound of the present disclosure, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactidepolyglycolide. Depending upon the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectablePage 28 of 6913238167vlAttorney Docket No. 2012034-0398formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

[0114] In some embodiments, provided pharmaceutically acceptable compositions are formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, pharmaceutically acceptable compositions described herein are administered without food. In other embodiments, pharmaceutically acceptable compositions described herein are administered with food. Pharmaceutically acceptable compositions described herein may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, earners commonly used include lactose and com starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.

[0115] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and / or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and / or i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

[0116] Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other Page 29 of 6913238167vlAttorney Docket No. 2012034-0398coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like.

[0117] The active compounds can also be in micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0118] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1.3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.EXEMPLARY EMBODIMENTSPage 30 of 6913238167vlAttorney Docket No. 2012034-03981. A method of treating a treating a disease, disorder, or condition by inhibiting KAT6A and KAT6B, the method comprising administering to a subject Compound 1Compound 1or a pharmaceutically acceptable salt thereof.2. The method of embodiment 1, wherein the disease, disorder, or condition is a cancer.3. The method of embodiment 2, wherein the subject has a tumor derived from the cancer.4. The method of embodiments 2 or 3, wherein the cancer is ovarian cancer, prostate cancer, or non-small cell lung cancer (“NSCLC”).5. The method of embodiments 3 or 4, wherein the volume of the tumor size has decreased from at least about 50% to about 150% of its size at baseline.6. The method of any one of embodiments 1-5, wherein the subject is administered a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient, or diluent.7. The method of any one of embodiments 1-6, wherein Compound 1 is administered orally.8. The method of any one of embodiments 1-7, wherein Compound 1 is administered once every other day, once per day, twice per day, once per week, twice per week, or once per month.9. The method of any one of embodiments 1-8, wherein Compound 1 is administered in an amount that is from about 0.5 mg to about 1000 mg per dose.Page 31 of 6913238167vlAttorney Docket No. 2012034-039810. The method of any one of embodiments 1-9, wherein the subject has previously received an alternative anti-cancer treatment.11. The method of embodiment 10, wherein the alternative anti-cancer treatment is selected from an androgen receptor antagonist, a tyrosine kinase inhibitor, an mTOR inhibitor, a PARP inhibitor, a taxoid agent, and an antineoplastic agent.12. The method of any one of embodiments 1-11, further comprising administering to the subject a second agent.13. The method of embodiment 12, wherein the second agent is a selective estrogen receptor modulator (SERM), a selective estrogen receptor degrader (SERD), a CDK4 / 6 inhibitor, a CDK4-selective inhibitor, a PI3 kinase inhibitor, an aromatase inhibitor, an mTOR inhibitor, an antibody to or inhibitor of PD-1, PD-L1 or CTLA-4, antibody to or inhibitor of EGFR, PDGFR, or IGFR, a USP1 inhibitor, an AKT inhibitor, a PARP inhibitor, a taxoid agent, or an antineoplastic agent.14. A method of treating a cancer comprising administering to a subject Compound 1Compound 1or a pharmaceutically acceptable salt thereof, wherein the cancer is ovarian cancer, prostate cancer, or non-small cell lung cancer.15. The method of embodiment 14, wherein the subject has a tumor derived from the cancer.16. The method of embodiments 14 or 15, wherein the volume of the tumor size has decreased from at least about 50% to about 150% of its size at baseline.Page 32 of 6913238167vlAttorney Docket No. 2012034-039817. The method of any one of embodiments 14-16, wherein the subject is administered a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient, or diluent.18. The method of any one of embodiments 14-17, wherein Compound 1 is administered orally.19. The method of any one of embodiments 14-18, wherein Compound 1 is administered once every other day, once per day, twice per day, once per week, twice per week, or once per month.20. The method of any one of embodiments 14-19, wherein Compound 1 is administered in an amount that is from about 0.5 mg to about 1000 mg per dose.21. The method of any one of embodiments 14-20, wherein the subject has previously received an alternative anti-cancer treatment.22. The method of embodiment 21, wherein the alternative anti-cancer treatment is selected from an androgen receptor antagonist, a tyrosine kinase inhibitor, an mTOR inhibitor, a PARP inhibitor, a taxoid agent, and an antineoplastic agent.23. The method of any one of embodiments 14-22, further comprising administering to the subject a second agent.24. The method of embodiment 23, wherein the second agent is a selective estrogen receptor modulator (SERM), a selective estrogen receptor degrader (SERD), a CDK4 / 6 inhibitor, a CDK4-selective inhibitor, a PI3 kinase inhibitor, an aromatase inhibitor, an mTOR inhibitor, an antibody to or inhibitor of PD-1, PD-L1 or CTLA-4, antibody to or inhibitor of EGFR, PDGFR, or IGFR, a USP1 inhibitor, an AKT inhibitor, a PARP inhibitor, a taxoid agent, or an antineoplastic agent.Page 33 of 6913238167vlAttorney Docket No. 2012034-039825. A method of inhibiting tumor growth in a subject suffering from a cancer, comprising administering to the subject Compound 1I / O 1 c 0l NHCompound 1or a pharmaceutically acceptable salt thereof, wherein the cancer is ovarian cancer, prostate cancer, or non-small cell lung cancer.26. The method of embodiment 25, wherein the subject is administered a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient, or diluent.27. The method of embodiments 25 or 26, wherein Compound 1 is administered orally.28. The method of any one of embodiments 25-27, wherein Compound 1 is administered once every other day, once per day, twice per day, once per week, twice per week, or once per month.29. The method of any one of embodiments 25-28, wherein Compound 1 is administered in an amount that is from about 0.5 mg to about 1000 mg per dose.30. The method of any one of embodiments 25-29, wherein the subject has previously received an alternative anti-cancer treatment.31. The method of embodiment 30, wherein the alternative anti-cancer treatment is selected from an androgen receptor antagonist, a tyrosine kinase inhibitor, an mTOR inhibitor, a PARP inhibitor, a taxoid agent, and an antineoplastic agent.32. The method of any one of embodiments 25-31, further comprising administering to the subject a second agent.Page 34 of 6913238167vlAttorney Docket No. 2012034-039833. The method of embodiment 32, wherein the second agent is a selective estrogen receptor modulator (SERM), a selective estrogen receptor degrader (SERD), a CDK4 / 6 inhibitor, a CDK4-selective inhibitor, a PI3 kinase inhibitor, an aromatase inhibitor, an mTOR inhibitor, an antibody to or inhibitor of PD-1, PD-L1 or CTLA-4, antibody to or inhibitor of EGFR, PDGFR, or IGFR, a USP1 inhibitor, an AKT inhibitor, a PARP inhibitor, a taxoid agent, or an antineoplastic agent.EXAMPLES

[0119] The foregoing description as well as the examples that follow are intended to illustrate and in no way limit the scope of the disclosure. As described in the illustrative examples below, in certain exemplary embodiments, compounds are prepared according to the following general procedures. This disclosure, unless otherwise indicated, utilizes conventional techniques of organic synthesis, characterization, in-vitro analytical techniques and assays, preclinical studies and models, and the like, which are understood by those skilled in the art(s) to which this disclosure pertains, and can be found in the literature.Materials and Methods

[0120] Compound 1, 5-((lH-pyrazol- l-yl)methyl)-6-methoxy-N-((2,4,6-trimethoxyphenyl) sulfonyl)picolinamide, was prepared as described in PCT Patent Application Publication No. WO2024 / 189598, Example 10.

[0121] Cell lines: VCaP (vertebral-cancer of the prostate) epithelial cells were obtained from ATCC (CRL-2876) and maintained in DMEM (Dulbecco’s Modified Eagle Medium) supplemented with 10% fetal bovine serum (FBS), (Gibco). LnCaP (FGC) cells (epithelial cell line derived from a human prostate carcinoma) were obtained from ATCC (CRL-1740) and maintained in RPMI-1640 medium supplemented with 10% FBS and GlutaMAX™ (Gibco). OAW28 human ovarian carcinoma cells were obtained from ECACC and maintained in DMEM supplemented with 10% FBS, GlutaMAX™ (Gibco), sodium pyruvate, and 0.7pg / ml bovine insulin. OVCAR3 human ovarian cancer cells were obtained from ATCC (HTB-161) and maintained in RPMI 1640 media supplemented with 20% FBS, GlutaMAX™ (Gibco) and 0.01 pg / ml human insulin. LCLC-97TM1 (human large cell lung carcinoma) cells were obtained fromPage 35 of 6913238167vlAttorney Docket No. 2012034-0398DSMZ (ACC-388) and maintained in RPMI 1640 supplemented with 20% FBS and GlutaMAX™ (Gibco). NCI-H1648 (human non-small cell lung cancer) cells were obtained from ATCC (CRL-5882) and maintained in RPMI 1640 supplemented with 5% FBS and GlutaMAX™ (Gibco).22Rvl (CRL-2505) (human prostate cancer) cells were obtained from ATCC and maintained in RPMI 1640 supplemented with 10% FBS and GlutaMAX™ (Gibco).EXAMPLE 1In Vitro Analysis: Inhibition of KAT Enzymes and Inhibition of Cancer Cell Proliferation by Compound 1

[0122] TR-FRET (time-resolved fluorescence resonance energy transfer) biochemical activity studies of Compound 1 were carried out against various enzymes, including KAT5, KAT6A, KAT6B, KAT7, and KAT8. DMSO solutions of Compound 1 were prepared for evaluation.KAT Enzymatic TR-FRET Assays - KAT6 Inhibition Selectivity

[0123] The potency of Compound 1 in inhibiting KAT enzymes was assessed using time-resolved fluorescence resonance energy transfer (TR-FRET), which is a homogenous proximity assay. Data provided are representative of experiments performed at least three separate times.

[0124] Recombinant KAT enzymes (MYST domain) KAT5, KAT6A, KAT6B, KAT7, and KAT8 were incubated with Compound 1, biotin-labelled histone H4 peptide, acetyl CoA and a europium-labelled anti-acetyl lysine antibody. The europium-labelled anti-acetyl lysine antibody is used as the donor fluorophore and binds to acetylated biotin labeled H4 peptide, following catalysis by the KAT enzyme. A streptavidin labelled APC acceptor fluorophore binds to the biotin and therefore when in proximity, the interaction of two fluorophore-labelled binding partners is detected by the energy transfer between the donor and acceptor fluorophores. This was measured in TR-FRET mode at 340 nm excitation and 615 and 665 nm emission on a Victor 5 (Perkin Elmer) plate reader.

[0125] The results of the assay are provided in the table below.Table 1:KAT5 KAT6A KAT6B KAT7 KAT8 IC50(nM) 6792 9 2 130 5444Page 36 of 6913238167vlAttorney Docket No. 2012034-0398

[0126] FIGs. 1A-1E are plots illustrating percent inhibition of KAT6A (FIG. 1A), KAT6B (FIG. IB), KAT7 (FIG. 1C), KAT5 (FIG. ID), and KAT8 (FIG. IE) by Compound 1. As shown by the above results, Compound 1 is a potent inhibitor of both KAT6A and KAT6B. Moreover, Compound 1 shows greater than 250-fold selectivity for KAT6A and KAT6B over proteins KAT5 and KAT8. Compound 1 exhibited some inhibitory properties of KAT7. In brief, this data illustrates that Compound 1 is a potent KAT6A and KAT6B- selective inhibitor.Cell Proliferation Assays: Ovarian, Prostate and Lung Cancer Cell Lines

[0127] An optimized number of cells per well were plated into tissue-culture treated opaque 96-well plates in complete media and incubated for 24-48 hours until the expected morphology was observed. Cells were treated with ligands for 7-21 days and proliferation measured using CellTiterGlo® (CTG), CellTiterGlo® 2.0 (Promega), or CyQuant (Invitrogen) reading luminescence using Spark (Tecan), Cytation V (Agilent) or CLARIOstar (BMGLabtech) plate readers. At the time of dosing, a T=0 plate was treated with CTG or frozen until analysis with CyQuant, and used as control to determine the GIso values. Media and compounds were refreshed every 4 to 7 days depending on the cell line. Final timepoint plates were assayed with CTG or CyQuant to measure cell number.Table 2.Cell Line Plating Density (cells / well) Assay DurationLNCaP (FGC) 1000 (96-wp) 14 daysVCaP 8000 (96-wp) 14 daysOAW28 3000 (96-wp) 14 daysOVCAR3 1500 (96-wp) 12 daysNCI-H1648 1500 (96-wp) 7 daysLCLC-97TM1 1200 (96-wp) 10 daysHCC2218 1000 (96-wp) 14 daysHCC70 1500 (96-wp) 12 days

[0128] Using the measurements [time zero (To) on Day 1, control growth DMSO (C) on Day end, and test growth in the presence of Compound 1 at the nine concentration levels (Ti) on Day End], the percentage growth at each of the drug concentrations was calculated. The percentage growth inhibition calculation formula used is given below:[(T-To) / (C-To)] x 100 for concentrations for which Ti> / =ToPage 37 of 6913238167vlAttorney Docket No. 2012034-0398[(Ti-To)ZTo] x 100 for concentrations for which Ti< To.Three dose response parameters can be calculated for each experimental agent as follows:Growth inhibition 50% (GI50): Concentration of the compound resulting in 50% reduction in luminescence in treated cells when compared with control cells (DMSO)[(Ti-To) / (C-To)] x 100 = 50Lethal concentration 50% (LC50): Concentration of the compound resulting in 50% reduction in luminescence at the end of drug treatment compared to that at the beginning, indicating a net loss of cells following treatment[(Ti-To) / To] x 100 = -50Total Growth Inhibition: Concentration of the experimental agent resulting in total growth inhibition of cellsTi = To

[0129] Values for each of these three parameters were calculated if the level of activity was reached. Graphs were plotted using Graph Pad Prism (Version 7.0 or above) software using a four- parameter fit.

[0130] Inhibition of cell proliferation by Compound 1 in prostate (LnCaP (FGC), VCaP), ovarian (OAW28, OVCAR3), lung (LCLC97TM1, NCLH1648) ), and ER- / HER2+ breast (HCC2218) and triple negative breast (HCC1187 and HCC70) cancer cell lines is reported in the table below:Table 3.LNCaP NCI- LCLC- VCaP OAW28 OVCAR3 HCC2218 HCC1187 HCC70 (FGC) 111648 97TM1GI500.39 319 9 231 69.5 4.6 7028 38.8 431(nM)

[0131] FIG. 2A is a plot illustrating decrease of proliferation of VCaP cells (prostate cancer) after exposure to varying concentrations of Compound 1.

[0132] FIG.2B is a plot illustrating decrease of proliferation of LCLC-97TM1 cells (lung cancer / NSCLC) after exposure to varying concentrations of Compound 1.

[0133] FIG.2C is a plot illustrating decrease of proliferation of OAW28 cells (ovarian cancer) after exposure to varying concentrations of Compound 1.Page 38 of 6913238167vlAttorney Docket No. 2012034-0398

[0134] FIG.2D is a plot illustrating decrease of proliferation of OVCAR3 cells (ovarian cancer) after exposure to varying concentration of Compound 1.

[0135] FIG.2E is a plot illustrating decrease of proliferation of LnCaP (FGC) cells (prostate cancer) after exposure to varying concentrations of Compound 1.

[0136] FIG.2F is a plot illustrating decrease of proliferation of NCI-H1648 cells (lung cancer / NSCLC) after exposure to varying concentrations of Compound 1.

[0137] Compound 1 inhibited proliferation of two androgen receptor (AR+) / androgen-sensitive prostate cell lines, LNCaP (FGC) and VCaP with nanomolar potency; LNCaP growth inhibition 50% (GI50) 0.39 nM and VCaP GI50319 nM.

[0138] Compound 1 inhibited proliferation of two high-grade serous ovarian cancer cell lines with GI50values of 9 and 231 nM, calculated for OAW28 and OVCAR3, respectively.

[0139] Compound 1 inhibited proliferation of NSCLC cell lines NCI-H1648 with a GI50of 69.5 nM and LCLC-97TM1 with a GI50of 4.6 nM.

[0140] The results in Table 3 illustrate that Compound 1 potently inhibits proliferation of multiple prostate, ovarian, NSCLC and triple negative breast cancer cell lines in vitro, with nanomolar potencies; and ER- / HER2+ breast cancer cell lines in vitro, with micromolar potencies.EXAMPLE 2In vivo analysis: Efficacy of Compound 1 and Ribociclib on Lung Cancer cells (LCLC-97TM1) in a Mouse Tumor Model

[0141] The in vivo efficacy of Compound 1 in combination with ribociclib was evaluated in a LCLC-97TM1 tumor model in female SCID Beige mice. LCLC-97TM1 cells (established by in vivo passage) were cultured at 37°C in an atmosphere of 5% CO2 in air. The tumor cells were routinely sub-cultured twice weekly. The cells grown in an exponential growth phase were harvested and counted for tumor inoculation.

[0142] Mice used in the study were SCID Beige mice, female, 6-8 weeks, weighing approximately 18-22 g.

[0143] Tumor Cell Inoculation: Each mouse was inoculated subcutaneously at the right flank with LCLC-97TM1 (10X106+Matrigel) cells for tumor development. The animals were randomized, and treatment was started when the average tumor size reached approximately 100- Page 39 of 6913238167vlAttorney Docket No. 2012034-0398150 mm3for the efficacy study. The test article administration and the animal numbers in each group are shown in the following experimental design table.

[0144] Assignment to the Groups: Before commencement of treatment, all animals were weighed, and the tumor volumes were measured. Mice were assigned into groups using randomized block design based upon their tumor volumes. The tumor size and bodyweight were measured twice per week after the randomization.Table 4. Groups and TreatmentDosageGroup N Treatment Route(mg / kg)1 7 Vehicle - PO QD2 7 Compound 1 1 PO QD3 7 Compound 1 3 PO QD4 7 Ribociclib 50 PO QDCompound 1 + PO QD +5 7 1 + 50Ribociclib PO QDCompound 1 + PO QD +6 7 3 + 50Ribociclib PO QD

[0145] Sample collection: Tumor samples from all groups were collected at 12h (3 mice) and 24h (4 mice) post last dose, 1 / 2 tumor was weighed and recorded, flash frozen and stored at -80 °C. Brain samples from all groups were collected at 12h (3 mice) and 24h (4 mice) post last dose, weighed, and recorded, flash frozen and stored at -80 °C.

[0146] Tumor size was measured twice per week in two dimensions using a caliper, and the volume was expressed in mm3using the formula: V = 0.5 a x b2where a and b are the long and short diameters of the tumor, respectively. The tumor volume was used for the calculations of T / C and TGI values. The T / C value (in percent) is an indication of antitumor effectiveness; T and C are the mean volume of the treated and control groups, respectively, on a given day.

[0147] TGI was calculated for each group using the formula: TGI (%) = [1-(Ti-T0) / (Vi-V0)] ×100; Ti is the average tumor volume of a treatment group on a given day, To is the average tumor volume of the treatment group on the first day of treatment, Vi is the average tumor volume of the vehicle control group on the same day with. and Vo is the average tumor volume of the vehicle group on the first day of treatment. All mice were euthanized after 12 and 24h post last day of dosing. Results are provided in FIGs. 3A-3D.Page 40 of 6913238167vlAttorney Docket No. 2012034-0398

[0148] FIG.3A is a plot illustrating the change in LCLC-97TM1 tumor volume over the treatment duration for each of the treatment groups.

[0149] FIG.3B is a plot illustrating the percent change in body weight over time for mice in each of the treatment groups.

[0150] FIG.3C is a plot illustrating the change in LCLC-97TM1 tumor volume for individual mice in each of the treatment groups via a scatter plot.

[0151] FIG.3D is a bar graph illustrating percentage change in LCLC-97TM1 tumor volume from baseline on day 32 for individual mice in each of the treatment groups.

[0152] Compound 1 inhibited tumor growth in the illustrative lung cancer model at both doses. In combination, Compound 1 and ribociclib demonstrated synergy and enhanced anti-tumor activity.EXAMPLE 3In Vivo Analysis: Efficacy of Compound 1 on Ovarian cancer cells in an OVCAR3 Ovarian Cancer Mouse Model

[0153] The present example evaluates the in vivo anti-tumor efficacy of Compound 1 on OVCAR3 ovarian cancer cells in a OVCAR3 tumor model in female Balb / c nude mice. The mice were dosed according to the following regimen:Table 5.DoseGroup N Treatment Route Frequency Duration (mg / kg)1 7 Vehicle — PO QD 28 Days2 7 Compound 1 1 PO QD 28 Days3 7 Compound 1 3 PO QD 28 DaysMaterials and Methods

[0154] Cell Culture: The OVCAR3 cells were maintained in vitro in RPMI 1640 medium supplemented with 20% fetal bovine serum, 0.01 mg / ml bovine insulin and 1% Antibiotic-Antimycotic at 37°C in an atmosphere of 5% CO₂ in air. The tumor cells were routinely subcultured twice weekly.Page 41 of 6913238167vlAttorney Docket No. 2012034-0398

[0155] Tumor Inoculation, Grouping and Treatment: Each mouse was inoculated subcutaneously at the right flank with OVCAR3 cells (10 x 106) in 0.2 mL of PBS mixed with Matrigel (50:50) for tumor development. Animals were randomized and allocated to treatment groups when the average tumor volume reached 142 mm3on Day 38 after cell inoculation, after which the treatment was begun on PG-D1. simply referred as Day 1.

[0156] Tumor Measurements and Endpoints: The major endpoint was to evaluate the effects of test articles on delay in tumor growth and / or tumor regression. Tumor size was measured twice a week in two dimensions using a caliper, and the volume was expressed in mm3using the formula: V = 0.5 a x b2where a and b are the long and short diameters of the tumor, respectively. The tumor volume was then used for calculations of the T / C value. The T / C value (in percent) is an indication of antitumor effectiveness; T and C are the mean volumes of the treated and control groups, respectively, measured on the same day. Tumor Growth Index (TGI) was calculated for each group using the formula: TGI (%) = [1-(Ti-To) / (Vi-Vo)] xlOO; Ti is the average tumor volume of a treatment group on a specified day. To is the average tumor volume of the treatment group on the first day of treatment, Vi is the average tumor volume of the Isotype control group on the same day with T, and Vo is the average tumor volume of the Isotype control group on the first day of treatment. All mice of groups were euthanized on D28, plasma, tumor and brain samples were collected.

[0157] FIG.4A is a plot illustrating the change in OVCAR3 tumor volume over the treatment duration for the different treatment groups.

[0158] FIG.4B is a plot illustrating the percent change in body weight over time for mice in each of the treatment groups.

[0159] In a second study, the in vivo anti-tumor efficacy of Compound 1 on OVCAR3 ovarian cancer cells in a tumor model in female Balb / c nude mice was investigated. The mice were dosed according to the following regimen:Table 6.DoseGroup N Treatment Route Frequency Duration (mg / kg)1 8 Vehicle — PO QD 28 days 2 8 Compound 1 0.5 PO QD 28 days 3 8 Compound 1 1 PO QD 28 daysPage 42 of 6913238167vlAttorney Docket No. 2012034-0398Materials and Methods

[0160] Cell Culture: The OVCAR3 cells were maintained in vitro in RPMI 1640 medium supplemented with 20% fetal bovine serum, 0.01 mg / ml bovine insulin and 1% Antibiotic-Antimycotic at 37°C in an atmosphere of 5% CO₂ in air. The tumor cells were routinely subcultured twice weekly.

[0161] Tumor Inoculation, Grouping and Treatment: Each mouse was inoculated subcutaneously at the right flank with OVCAR3 cells (10 x 106) in 0.2 mL of PBS mixed with Matrigel (50:50) for tumor development. Animals were randomized and allocated to treatment groups when the average tumor volume reached 141 mm3on Day 38. Treatment started on Day 1.

[0162] Tumor Measurements and Endpoints: The major endpoint was to evaluate the effects of test articles on delay in tumor growth and / or tumor regression. Tumor size was measured twice a week in two dimensions using a caliper, and the volume was expressed in mm3using the formula: V = 0.5 a x b2where a and b are the long and short diameters of the tumor, respectively. The tumor volume was then used for calculations of the T / C value. The T / C value (in percent) is an indication of antitumor effectiveness; T and C are the mean volumes of the treated and control groups, respectively, measured on the same day. Tumor Growth Index (TGI) was calculated for each group using the formula: TGI (%) = [1-(Ti-To) / (Vi-Vo)] xlOO; Ti is the average tumor volume of a treatment group on a specified day, TO is the average tumor volume of the treatment group on the first day of treatment, Vi is the average tumor volume of the Isotype control group on the same day with T. and Vo is the average tumor volume of the Isotype control group on the first day of treatment. All mice of groups were euthanized on Day 28 / 29.

[0163] FIG.5A is a plot illustrating the change in OVCAR3 tumor volume over the treatment duration for each of the treatment groups.

[0164] FIG.5B is a plot illustrating the percent change in body weight over time for mice in each of the treatment groups.

[0165] Compound 1 as a single agent demonstrated robust inhibition of tumor growth in the OVCAR3 xenograft ovarian cancer model. At doses of both 0.5 and 1 mg / kg, tumor regression was observed, which was sustained across the 28-day study period.Page 43 of 6913238167vlAttorney Docket No. 2012034-0398EXAMPLE 4In vivo Analysis: Efficacy of Compound 1 in Combination with Docetaxel on Prostate Cancer Cells in a 22RV1 Prostate Cancer Mouse Model

[0166] The in vivo anti-tumor efficacy of Compound 1, alone and in combination with docetaxel (standard of care agent), on 22RV 1 prostate cancer cells was evaluated in a prostate cancer tumor model in male Balb / c nude mice. In addition, the efficacy of docetaxel as a monotherapy was evaluated. The mice were dosed according to the following regimen:Table 7.Duration Dose LevelGroup N Treatment Route Frequency (maximum (mg / kg)of) 1 7 Vehicle — PO QD 38 days 2 7 Compound 1 1 PO QD 38 days 3 7 Compound 1 3 PO QD 38 days 4 7 Docetaxel 10 IP QW 38 days 5 7 Compound 1 + Docetaxel 1+10 PO + IP QD + QW 38 days 6 7 Compound 1 + Docetaxel 3+10 PO + IP QD + QW 38 days

[0167] Cell Culture: 22Rvl (ATCC-CRL-2505) cells were cultured at 37°C in an atmosphere of 5% CO₂ in air. The tumor cells were routinely subcultured twice weekly. The cells growing in an exponential growth phase were harvested and counted for tumor inoculation.

[0168] Tumor Inoculation, Grouping and Treatment: Each mouse was inoculated subcutaneously at the right flank with 22RV 1 cells (5 x 106) in 0.2 mL of PBS mixed with Matrigel (50:50) for tumor development. Treatment started on Day 1 when the average tumor volume reached approximately 100 mm3.Tumor Measurements and Endpoints: Tumor size was measured twice per week in two dimensions using a caliper, and the volume was expressed in mm3using the formula: V = 0.5 a x b2where a and b are the long and short diameters of the tumor, respectively. The tumor volume was then used for the calculations of T / C and TGI values. The T / C value (in percent) is an indication of antitumor effectiveness; T and C are the mean volume of the treated and control groups, respectively, on a Page 44 of 6913238167vlAttorney Docket No. 2012034-0398given day. TGI was calculated for each group using the formula: TGI (%) = [1-(Ti-To) / (Vi-Vo)] xlOO; Tj is the average tumor volume of a treatment group on a given day, To is the average tumor volume of the treatment group on the first day of treatment, Vi is the average tumor volume of the vehicle control group on the same day with Ti, and V0 is the average tumor volume of the vehicle group on the first day of treatment. All mice were euthanized after 4 and 24h post last day of dosing.

[0169] FIG.6A is a plot illustrating the change in 22Rvl tumor volume over the 38 day treatment duration for each of the treatment groups.

[0170] FIG.6B is a plot illustrating the change in 22Rvl tumor volume on day 38 for individual mice in each of the treatment groups (scatter plot).

[0171] FIG.6C is a bar graph illustrating percentage change in 22Rvltumor volume on day 32 from baseline for individual mice in each of the treatment groups.

[0172] As can be seen, Compound 1 inhibited tumor growth in a dose-dependent manner in the 22Rvl CDX, an AR+ prostate cancer model; moreover, combining Compound 1 (1 mg / kg) with the standard of care agent, docetaxel, resulted in enhanced anti-tumor activity.

[0173] The illustrative examples and results provided above indicate that Compound 1 is effective to inhibit proliferation of multiple prostate, ovarian, and non-small cell lung cancer cell lines in vitro, with nanomolar potencies. Additionally. Compound 1, when administered as a monotherapy, demonstrated anti-tumor activity in prostate, ovarian, and NSCLC xenograft models. In an exemplary OVCAR3 model, Compound 1 monotherapy resulted in sustained tumor regression. In combination with standard of care therapeutics, for example, docetaxel, Compound 1 demonstrated synergy and enhanced tumor growth inhibition in 22RV1 (prostate) and LCLC-97TM1 (NSCLC) xenografts.EXAMPLE 5In-vitro and In-Vivo Characterization of KAT6 Inhibitor Compounds in Preclinical Models of ER+ Breast CancerMaterials and Methods

[0174] Biochemical assays: Compounds were serially diluted and incubated with KAT proteins. Biotinylated Histone-H4 protein and Acetyl-CoA were added, and samples were further Page 45 of 6913238167vlAttorney Docket No. 2012034-0398incubated for 60 minutes. Plates were read in TR-FRET mode (Ex: 340 nm, Em:615 and 665 nm) post-addition of the detection mix containing Eu anti-acetyl lysine antibody and streptavidin- APC.

[0175] Cell proliferation assays: Cells were plated in 96-wp at optimized densities in appropriate complete medium and incubated overnight before being treated with serial dilutions of compounds for 7, 10 or 14 days. Cell number was assessed using CTG and normalized to T=0.

[0176] Drug combination analysis: Synergism was evaluated using the Zero Interaction Potency (ZIP) model, assuming that the combined effect of two molecules is the sum of their individual responses, without any interaction. Combinations were normalized to the monotherapy response. Deviations from this predicted combined effect indicate either synergy (greater effect relative to a predicted combined effect) or antagonism (lesser effect relative to a predicted combined effect). Deviations of greater than 10 from the predicted combined effect indicate synergy; between -10 and +10 indicate additive effect, and less than 10 indicates antagonism.

[0177] Cellular pharmacodynamic assays: Cells were plated at an optimized density in appropriate complete medium and incubated overnight. Compounds were serially diluted and dosed to cells which were incubated at 37°C, 5% CO₂ for 24 hours or 5 days. Cells were lysed and samples analyzed by western blotting using antibodies specific to H3K23Ac, Histone-H3, ERa and P-actin.

[0178] Xenograft studies: Female, immune deficient NOD SCID mice were supplemented with estradiol and implanted with an ER+ breast cancer cell line, ZR-75-1, subcutaneously in the mammary fat region and were randomized into groups when the tumor volume reached -150 mm3. Mice were treated for 25 days with either vehicle or Compounds at 0.1, 0.3 or 1 mg / kg.

[0179] Compounds 1-5 were characterized as described below.

[0180] Structures and chemical names for Compounds 2-5 are provided below.Page 46 of 6913238167vlAttorney Docket No. 2012034-0398Compound 25-((1H-pyrazol-1-yl)methyl)-N-((2,6-dimethoxyphenyl)sulfonyl)-6-methoxypicolinamideCompound 35-((1 H-pyrazol-1 -yl)methyl)-6-methoxy- / V-((2-methoxy-6- (trifluoromethoxy)phenyl)sulfonyl)picolinamideCompound 45-((1H-pyrazol-1-yl)methyl)-N-((4-fluoro-2,6-dimethoxyphenyl)sulfonyl)-6-methoxypicolinamideCompound 55-((1H-pyrazol-1-yl)methyl)-N-((2,6-dimethoxy-4-methylphenyl)sulfonyl)-6-methoxypicolinamide

[0181] A. Biochemical Potency Assays Measuring Inhibition of KAT Enzymes. Biochemical potencies of KAT6-targeting inhibitor compounds 1-5 were determined as described above. Assay results are provided in Table 8.Table 8.Compound Compound Compound Compound Compound Page 47 of 6913238167vlAttorney Docket No. 2012034-03981 2 3 4 5 KAT6A IC50, nM 9 12 13 14 14 KAT6B IC50, nM 1 2 0.5 3 3 KAT5 IC50, nM 6792 8619 >10,000 >10,000 9929 KAT7 IC50, nM 130 55 711 578 180KAT8 IC50, nM 5444 >10,000 >10,000 >10,000 3764

[0182] As illustrated by the results in Table 8. Compounds 1-5 are potent against KAT6A and KAT6B (<20 nM). The data for Compound 1 also appears above in Example 1. As shown above, the compounds exhibited greater than 250-fold selectivity over other KAT family members, in particular, proteins KAT5 and KAT8.

[0183] B. Cell Proliferation Assays Measuring Inhibition of Proliferation of KAT6-amplified ZR-75-1, an ER+ Breast Cancer Cell Line. Compounds 1-5 potently inhibit ZR-75-1 breast cancer cell proliferation, with observed GI50 values in the nanomolar or lower range. Results are provided in Table 9 below.Table 9.Compound Compound Compound Compound Compound 1 2 3 4 5GI50, nM 0.30 0.40 1.75 0.14 0.26

[0184] C. Cell Proliferation Assays Measuring Inhibition of Proliferation in both ESRI wild type (WT) and Mutant Breast Cancer Cell Lines. In KAT6 overexpressing ER+ breast cancer cell lines, T47D and CAMA-1, Compounds 1, 4, and 5 strongly inhibited cell proliferation. KAT6-low MCF7 cells were not sensitive to the test inhibitor compounds. Proliferation of ESRI mutant D538G and Y537S CAMA-1 cells was inhibited by Compounds 1, 4, and 5, supporting the efficacy of these KAT6 inhibitors in treating ESRI mutant breast cancer. Growth inhibition values (GI50) for the KAT6 inhibitor compounds 1, 4, and 5 on cell proliferation are provided in Table 10 below.Table 10.Compound Compound Compound1 4 5T47D GI50, nM 6.5 11 0.8CAMA-1 GI50, nM 4.6 92 5.3CAMA-1 D538G GI50, nM 1.8 3.4 3.0CAMA-1 Y537S GI50, nM 3.2 0.2 6.6Page 48 of 6913238167vlAttorney Docket No. 2012034-0398MCF7 GI50, nM >10,000 >10,000 >10,000

[0185] D. Western Blot Analysis of Compounds 1, 4 and 5 on H3K23Ac in ZR-75-1 and CAMA-1 cells. Western blot analysis of Compounds 1, 4 and 5 on H3K23Ac in ZR-75-1 and CAMA-1 cells was earned out; Compounds 1, 4, and 5 demonstrate strong concentrationdependent target engagement leading to inhibition of histone 3 lysine 23 acetylation (H3K23Ac). These data indicate that the illustrative compounds strongly engage histone target in ZR-75-1 and CAMA cells. Results are provided in Table 11.Table 11. Inhibition of H3K23AcCompound Compound Compound1 4 5ZR-75-1, IC50, nM 496 18 207CAMA-1 IC50, nM 341 389 87

[0186] E. Reduction in ERa Protein Levels in ZR-75-1 Cells: Western blot analysis was carried out to investigate ERa protein levels for ZR-75-1 cells treated with Compounds 1, 4, and 5. Treatment of the cells with Compounds 1, 4 and 5 resulted in a significant reduction in ERa protein levels, illustrating an induction of downstream gene expression changes subsequent to target engagement. Results (ZR-75-1 ERa levels) were as follows: Compound 1: 84% at 13 nM; Compound 4: 66% at 13 nM; Compound 5: 86% at 13 nM.

[0187] F. Xenograft studies in Mice Implanted with an ER+ Breast Cancer Cell Line, ZR-75-1: In a 25-day breast cancer xenograft study conducted as described above, the ability of Compounds 1, 4, and 5 to inhibit breast tumor growth and / or cause tumor regression in vivo was investigated. Prifetrastat, a KAT6A / B inhibitor compound, was used as a positive control. A plot of mean tumor volume versus day of dosing for the various treatment groups is shown in FIG. 7A (with the legend as provided with FIG. 7B); FIG. 7B is a scatter plot of tumor volume at day 25 for the various treatment groups.

[0188] Compounds 1, 4 and 5 caused dose-dependent tumor growth inhibition and tumor regression either comparable to or better than the positive control; additionally, the compounds were found to be well-tolerated, and no significant body weight changes were observed among different treatment groups compared to vehicle.

[0189] Administration of Compound 1 resulted in statistically significant anti-tumor efficacy in ZR-75-1 xenograft tumors at all tested dose levels. At the end of the 25-day dosing period, once Page 49 of 6913238167vlAttorney Docket No. 2012034-0398daily administration of Compound 1 at 0.1 mg / kg, 0.3 mg / kg and 1 mg / kg produced significant dose-dependent tumor growth inhibition (TGI) values of 84.36%, 124.29% and 138.50%, respectively. Treatment with Compound 1 at 0.3 mg / kg and 1 mg / kg for 25-days resulted in tumor regression.

[0190] G. Pharmacokinetic Studies in Mouse, Rat and Dog: Compounds 1, 4, and 5 were administered orally to CD-I mice, Wistar rats, and beagle dogs. Pharmacokinetic data is provided in Table 12 below.Table 12.Species CD-I Mice Wistar Rat Beagle Dog Dose (mg / kg) 10 10 3Compound 1 4 5 1 4 5 1 5 AUC(0-last)286800 152726 250519 207906 160531 265421 1071885 906987 (ng*hr / mL)T1 / 2(hr) 6.8 2.9 3.4 2.6 3.5 22.3 24.3 (MRT) (MRT) Cmax 29214 22181 34176 32042 12687 29544 29082 23355 (ng / mL)% F 62 78 84 100 72 81 -100 >100Cave(free) / GI50 345 313 108At 1 mg / kgMRT = mean residence time.

[0191] Upon oral administration, the exemplary compounds, Compounds 1, 4 and 5, demonstrated good oral bioavailability with long half-lives and slow clearance. Compounds 1, 4, and 5 dosed at 1 mg / kg in mice, were calculated to demonstrate greater than 100-fold of the GI50 atC ave (free).

[0192] Drug Combination and Synergism Analysis in an ER+ and KAT6-Overexpressing Cell Line, T47D: The possibility of synergism was explored as described above for the following combinations: (i) Compound 1 and a CDK4 / 6 inhibitor, palbociclib, and (ii) Compound 1 and a complete estrogen receptor antagonist, palazestrant. The inhibition of T47D cell proliferation by Compound 1 alone, and in combination with either palezestrant or palbociclib, at different concentrations, was investigated. In combination with the complete estrogen receptor antagonist,Page 50 of 6913238167vlAttorney Docket No. 2012034-0398palazestrant, dose-dependent synergism was observed at the 1 nM concentration (FIG. 8A). Compound 1 exhibited synergy in a dose-dependent manner at all concentrations tested with the CDK4 / 6 inhibitor, palbociclib (FIG. 8B). Synergy scores for the combination of Compound 1 and palazestrant are shown in FIG. 9A; synergy scores for the combination of Compound 1 and palbociclib are shown in FIG. 9B.

[0193] The data from this example illustrate that Compounds 1, 2, 3, 4, and 5 are highly potent against KAT6A / B and are highly selective in contrast to inhibition of KAT5 and KAT8 proteins. In KAT6-amplified and overexpressing breast cancer cell lines, Compounds 1, 4, and 5 demonstrated target engagement and efficacy. Compounds 1, 4, and 5 showed tumor regression in a KAT6-amplified ER+ breast cancer mouse model. In vivo (mouse) assessment of Compounds 1, 4, and 5 showed high levels of free drug exposure. Additionally, Compound 1 showed synergism with a CDK4 / 6 inhibitor (palbociclib) and with a complete estrogen receptor antagonist (palazestrant).EXAMPLE 6In Vitro Study of a KAT6 Inhibitor Compound in Combination with Anti- Estrogens and CDK4 / 6 Inhibitors to Inhibit Proliferation of an ESR1WTER+Breast Cancer Cell Line

[0194] Cell proliferation assays: T47D cells were plated in 96- well plates at 1000 cells / well in complete medium and incubated overnight. Cells were treated with serial dilutions of Compound 1 plus fixed concentrations of fulvestrant, palazestrant, and / or ribociclib the presence of 100 pM estradiol for 10 days. Cell number was assessed using CellTiter-Glo® 2.0 and normalized to T=0.

[0195] Drag combination analysis: Synergy was evaluated using SynergyFinder3.0 tools, specifically the Zero Interaction Potency (ZIP) model, which assumes that the combined effect of two molecules is the sum of their individual responses without any interaction. Combinations were normalized to the monotherapy response; deviations greater than 10 from this predicted combined effect indicate synergy (greater effect), between -10 and +10 indicate additive (equal) effect, and less thanlO indicates antagonism (lesser effect).

[0196] FIGs. 10A-C are dose response curves of percent inhibition of T47D cell proliferation for various test articles, including combinations. FIG. 10A provides dose response curves for Compound 1 alone, fulvestrant alone at varying concentrations (0.1 nM, 1.0 nM, and 3.17 nM),Page 51 of 6913238167vlAttorney Docket No. 2012034-0398and Compound 1 in combination with different concentrations of fulvestrant. FIG. 10B provides dose response curve for Compound 1 alone, palazestrant alone at varying concentrations (0.1 nM, 1.0 nM, and 3.17 nM), and Compound 1 in combination with different concentrations of palazestrant. FIG. 10C shows dose response curves for Compound 1 alone, ribociclib alone at varying concentrations (16 nM, 63 nM, and 250 nM), and Compound 1 in combination with different concentrations of ribociclib. As illustrated in FIGs. 10A-C, the combination of Compound 1 with fulvestrant, palezestrant, or ribociclib enhanced inhibition of ER+ / HER2-, ESR1WTT47D cells over monotherapy.

[0197] Synergy analysis was carried out as described above. Synergy plots for the doublet combinations are provided in FIGs. 11A-C. FIG. 11A is a synergy plot for the combination of Compund 1 and fulvestrant. FIG. 11B is a synergy plot for the combination of Compound 1 and palazestrant. FIG. 11C is a synergy plot for the combination of Compound 1 and ribociclib. As shown, the synergy analysis indicated that Compound 1 acts synergistically when combined with an anti-estrogenic compound or with a CDK4 / 6 inhibitor.

[0198] Triplet combinations were also explored for inhibition of T47D cell proliferation. The triplet combinations included Compound 1 with fulvestrant (1 nM) and ribociclib (100 nM), and Compound 1 with palezestrant (1 nM) and ribociclib (100 nM). Dose-response curves are shown in FIGs. 12A (Compound 1, fulvestrant, ribociclib) and 12B (Compound 1, palazestrant, ribociclib). As shown, the combination of Compound 1 combined with both fulvestrant and ribociclib did not demonstrate additional anti-proliferative effects when compared to the doublet combinations in this assay. However, in contrast, the triplet combination of Compound 1 with palazestrant and ribociclib increased inhibition when compared to the doublet combination.

[0199] In sum, the foregoing assay results illustrate that Compound 1 is effective to inhibit cell proliferation and synergize with anti-estrogens such as fulvestrant and palazestrant and an illustrative CDK4 / 6 inhibitor, ribociclib. in a breast cancer cell line.EXAMPLE 7In Vivo Study of a KAT6 Inhibitor Compound in Combination with Anti- Estrogens and CDK4 / 6 Inhibitors in a (i) KAT6-overexpressing an ESR1WTER+ / HER2- Breast Cancer Cell Line-Derived Xenograft Model, T47D, and in a (ii) KAT6-Expressing ESR1WTER+ / HER2+ Patient-Derived Xenograft (PDX) Model, ST340Page 52 of 6913238167vlAttorney Docket No. 2012034-0398

[0200] Athymic, female nude mice (immune deficient) were supplemented with estradiol and implanted subcutaneously with an ER+ breast cancer cell line, T47D, or a patient-derived xenograft tumor fragment in the mammary fat region or flank. Mice were randomized into groups and when the tumor volume reached -150 mm3, were treated for at least 28 days with either vehicle or the indicated test group regimens. Prifetrastat, a KAT6A / B inhibitor compound, was used as a positive control comparator. Tumor growth inhibition (TGI) was investigated for combination therapies with a KAT6 inhibitor compound in a KAT6-overexpressing ESR1WTET+ / HER2’ breast cancer cell line-derived xenograft model, T47D.

[0201] Test articles included vehicle (i) monotherapies: fulvestrant (25 mg / kg), positive control (0.5 mg / kg), ribociclib (25 mg / kg), Compound 1 (0.5 mg / kg, 1 mg / kg), palazestrant (10 mg / kg): (ii) doublet combinations: positive control (0.5 mg / kg) + fulvestrant (25 mg / kg), positive control (0.5 mg / kg) + palazestrant (10 mg / kg), Compound 1 (0.5 mg / kg) + fulvestrant (25 mg / kg), Compound 1 (1.0 mg / kg) + fulvestrant (25 mg / kg), Compound 1 (0.5 mg / kg) + palazestrant (10 mg / kg): Compound 1 (1.0 mg / kg) + palazestrant (10 mg / kg); and (iii) triplet combinations: positive control (0.5 mg / kg) + fulvestrant (25 mg / kg) + ribociclib (25 mg / kg); Compound 1 (0.5 mg / kg) + fulvestrant (25 mg / kg) + ribociclib (25 mg / kg); Compound 1 (1.0 mg / kg) + fulvestrant (25 mg / kg) + ribociclib (25 mg / kg); Compound 1 (0.5 mg / kg) + palazestrant (10 mg / kg) + ribociclib (25 mg / kg); Compound 1 (1.0 mg / kg) + palazestrant (10 mg / kg) + ribociclib (25 mg / kg); positive control (0.5 mg / kg) + palazestrant (10 mg / kg) + ribociclib (25 mg / kg).

[0202] Tumor growth inhibition (TGI) for the various treatments is shown in FIGs. 13A-C. FIG. 13A is a scatter plot of tumor volume (mm2) at day 33 of treatment for the various treatment groups including monotherapy, doublet combinations and triplet combinations. FIG. 13B provides plots of tumor volume over time for both single agent therapies and combination therapies; FIG.13C is a waterfall plot illustrating percent change in tumor volume for monotherapies and combination therapies.

[0203] As shown, Compound 1 at 1 mg / kg demonstrated the most robust tumor growth inhibition as monotherapy among all agents tested in the KAT6-overexpressing ESR1WTER+ / HER2- breast cancer CDX model. Additionally, combination of fulvestrant with a KAT6 inhibitor, Compound 1 or the positive control, resulted in tumor growth inhibition but not tumor regression in a majority of the animals. Combination of palazestrant with Compound 1 or the positive control resulted in significant tumor regression in all animals. Finally, Compound 1 and Page 53 of 6913238167vlAttorney Docket No. 2012034-0398palazestrant combinations showed significantly improved anti-tumor efficacy compared to the positive control compound in combination with fulvestrant.

[0204] As described above, tumor growth inhibition (TGI) was also investigated for combination therapies with a KAT6 inhibitor compound in a patient-derived xenograft model, ST340.

[0205] Test articles included vehicle (i) monotherapies: fulvestrant (25 mg / kg), ribociclib (25 mg / kg), Compound 1 (3.0 mg / kg), palazestrant (5 mg / kg); (ii) doublet combinations: Compound 1 (3.0 mg / kg) + fulvestrant (25 mg / kg), Compound 1 (3.0 mg / kg) + palazestrant (5 mg / kg), Compound 1 (3.0 mg / kg) + ribociclib (25 mg / kg); and (iii) triplet combinations: Compound 1 (3.0 mg / kg) + fulvestrant (25 mg / kg) + ribociclib (25 mg / kg); Compound 1 (3.0 mg / kg) + palazestrant (5.0 mg / kg) + ribociclib (25 mg / kg).

[0206] Tumor growth inhibition (TGI) for the various treatments is shown in FIGs. 14A-C. FIG. 14A is a scatter plot of tumor volume (mm2) at day 28 of treatment for the various treatment groups including monotherapy, doublet combinations and triplet combinations. FIG. 14B provides plots of tumor volume over time for both single agent therapies and combination therapies; FIG.14C is a waterfall plot illustrating percent change in tumor volume for monotherapies and combination therapies.

[0207] Results from this study include the following. Addition of ribociclib to the combination of Compound 1 and palazestrant did not lead to an improved anti-tumor response in the T47D model. In a KAT6-expressing ESR1ER+ / HER2+ PDX model, administration of Compound 1 resulted in approximately 60% TGI as a monotherapy, while the combination of Compound 1 and palazestrant with or without ribociclib showed significantly improved antitumor efficacy relative to the monotherapy (TGI of 91% and 95%, respectively. All Compound 1 combinations were well- tolerated, with no significant changes in body weight and no mortality in either study.

[0208] In sum, the results from this example illustrate that treatment with Compound 1 led to either tumor growth inhibition or tumor regression in vivo in T47D and ST340 xenograft models across all treatment groups. Compound 1 showed robust synergistic anti-tumor activity when combined with either fulvestrant or palazestrant in doublet therapy, in both breast cancer CDX and PDX mouse models.Page 54 of 6913238167vlAttorney Docket No. 2012034-0398EXAMPLE 8In Human Phase 1 Study of Compound 1 to Evaluate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Early Signs of Clinical Activity of Compound 1 as Monotherapy and in Combination with Other Anticancer Agents with Certain Solid Tumors

[0209] The study consists of two parts: a dose escalation and a dose expansion.

[0210] Abbreviations: ER+ = estrogen receptor positive; HER2- = human epidermal growth factor receptor 2 negative; mBC = metastatic breast cancer; mCRPC = metastatic castrationresistant prostate cancer; NSCLC= non-small cell lung cancer; RDE = recommended dose / regimen for expansion.

[0211] Part 1A (Dose Escalation for Compound 1 Monotherapy): This part of the study evaluates the safety, tolerability, and PK in a range of doses of Compound 1, a lysine acetyltransferases 6A and 6B (KAT6A / B) inhibitor, administered orally once daily to participants with ER+ HER2- advanced or metastatic breast cancer (mBC), advanced or metastatic castration resistant prostate cancer (mCRPC), or advanced or metastatic non-small cell lung cancer (mNSCLC), and determines the maximum tolerated dose (MTD) and the recommended dose / regimen for expansion (RDE).

[0212] Part IB (Dose Escalation for Compound 1 in Combination with Fulvestrant): This part of the study evaluates the safety and PK of Compound 1 administered in combination with fulvestrant in participants with ER+ HER2- mBC, and determines MTD and RDE for the combination.

[0213] Part 1C (Dose Escalation for Compound 1 in Combination with Palazestrant): This part of the study evaluates the safety and PK of Compound 1 administered in combination with palazestrant in participants with ER+ HER2- mBC, and determines MTD and RDE for the combination.

[0214] Part 2A (Dose Expansion for Compound 1 Monotherapy): This part of the study evaluates two expansion cohorts at the monotherapy RDE from part 1 in participants with ER+ HER2- mBC and participants with mCRPC.

[0215] Part 2B (Dose Expansion for Compound 1 in Combination with Fulvestrant or Palazestrant): This part of the study evaluates the RDEs for Compound 1 in combination withPage 55 of 6913238167vlAttorney Docket No. 2012034-0398fulvestrant from Part IB OR the RDEs of Compound 1 in combination with palazestrant in an expansion cohort in participants with ER+ HER2- mBC.Key Inclusion Criteria:

[0216] Key inclusion criteria are as follows: participants with advanced or metastatic ER+HER2- breast cancer, mCRPC, or NSCLC (Part 1) or advanced or metastatic ER+HER2- BC or mCRPC (Part 2).

[0217] Part 1A (Dose escalation for Compound 1 monotherapy): Participants must have a tumor that is unresectable or metastatic and for which life prolonging measures do not exist or available therapies are intolerable or no longer effective.

[0218] Part IB (Dose escalation for Compound 1 in combination with fulvestrant): Participants with advanced or metastatic ER+ HER2- breast cancer that have progressed on or after at least 1 prior line of treatment that included endocrine therapy and CDK 4 / 6 inhibitor in advanced or metastatic setting and must have received no more than 2 prior lines of endocrine therapy (one of which must be in combination with a CDK4 / 6 inhibitor) and no more than 1 prior line of chemotherapy or an antibody-drug conjugate in the advanced or metastatic setting.

[0219] Part 1C (Dose escalation for Compound 1 in combination with palazestrant): Participants with advanced or metastatic ER+ HER2- breast cancer that have progressed on or after at least 1 prior line of treatment that included endocrine therapy and a CDK 4 / 6 inhibitor in an advanced or metastatic setting and must have received no more than 2 prior lines of endocrine therapy (one of which must be in combination with a CDK4 / 6 inhibitor) and no more than 1 prior line of chemotherapy or an antibody-drug conjugate in the advanced or metastatic setting.

[0220] Part 2A (Dose Expansion in ER+ HER2- mBC for Compound 1 monotherapy): Participants must have received up to 3 prior lines of endocrine therapy (one of which must be in combination with a CDK4 / 6 inhibitor) and up to 1 prior line of chemotherapy or an antibody-drug conjugate.

[0221] Part 2A (Dose Expansion in mCRPC for Compound 1 monotherapy): Participants must have received up to 4 lines of prior systemic therapy for prostate cancer. Prior therapy must include treatment with an androgen receptor pathway inhibitor(s).

[0222] Part 2B (Dose Expansion in ER+ HER2- mBC for Compound 1 in combination with fulvestrant or Dose Expansion in ER+ HER2- mBC for Compound 1 in combination with palazestrant): Participants must have progressed on or after at least 1 prior line of treatment that Page 56 of 6913238167vlAttorney Docket No. 2012034-0398included endocrine therapy and a CDK 4 / 6 inhibitor in an advanced or metastatic setting. Participants must have received no more than 2 prior lines of endocrine therapy in the advanced or metastatic setting and no more than 1 prior line of chemotherapy or an antibody-drug conjugate in the advanced or metastatic setting.Key Exclusion Criteria:

[0223] Key exclusion criteria are as follows: (i) prior therapy with a KAT6A / B inhibitor in any treatment setting; (ii) participants with advanced / metastatic, symptomatic, visceral spread, that are at risk of life-threatening complications in the short term; (iii) known active or symptomatic central nervous system (CNS) metastases, carcinomatous meningitis, leptomeningeal disease, or a spinal cord compression that require CNS-specific treatment, or participants who did not demonstrate clinical and radiologic stability during the last 2 months prior to the first dose of study treatment or require or are currently on steroid therapy for CNS metastases; history of cerebral vascular disease, including transient ischemic attack, within 6 months prior to the first dose of study treatment; history of or ongoing impaired cardiac function or clinically significant cardiac disease within 6 months prior to the first dose of study treatment; additional inclusion / exclusion criteria may apply.

[0224] The primary purpose of the study is treatment; the allocation of participants is randomized; the interventional model is sequential assignment; there is no masking (Open Label).Table 13A. Arms and InterventionsParticipant Group / Arm Intervention / T reatmentExperimental: Part 1A Dose Drug: Compound 1Escalation monotherapy Selective inhibitor of HAT enzymes KAT6Aand KAT6BExperimental: Part IB Dose Drug: Compound 1Escalation in combination with Selective inhibitor of HAT enzymes KAT6Afulvestrant and KAT6BDrug: FulvestrantSelective estrogen receptor degrader (SERD)Page 57 of 6913238167vlAttorney Docket No. 2012034-0398Participant Group / Arm In terven tion / T reatmentExperimental: Part 1C Dose Drug: Compound 1Escalation in combination with Selective inhibitor of HAT enzymes KAT6A palazestrant and KAT6BDrug: PalazestrantComplete estrogen receptor antagonist (CERAN)Experimental: Part 2A Dose Drug: Compound 1Expansion monotherapy - mBC Selective inhibitor of HAT enzymes KAT6A and KAT6BExperimental: Part 2 A Dose Drug: Compound 1Expansion monotherapy - Selective inhibitor of HAT enzymes KAT6A mCRPC and KAT6BExperimental: Part 2B Dose Drug: Compound 1Expansion in combination with Selective inhibitor of HAT enzymes KAT6A fulvestrant OR palazestrant- and KAT6BmBC @ RDE 1Drug: FulvestrantSelective estrogen receptor degrader (SERD) Drug: PalazestrantComplete estrogen receptor antagonist (CERAN)Experimental: Part 2B Dose Drug: Compound 1Expansion in combination with Selective inhibitor of HAT enzymes KAT6A fulvestrant OR palazestrant- and KAT6BmBC @ RDE 2Drug: FulvestrantSelective estrogen receptor degrader (SERD) Drug: PalazestrantComplete estrogen receptor antagonist (CERAN)Page 58 of 6913238167vlAttorney Docket No. 2012034-0398Table 13B. Primary Outcome MeasuresOutcome Measure Time FrameNumber of participants with dose-limiting toxicities in theDose Escalation Arms Up to 28 daysIncidence of adverse events and laboratory abnormalities Up to 26 monthsTable 13C. Secondary Outcome MeasuresOutcome Measure Time FrameMaximum observed concentration (Cmax) Up to 26 monthsTime to maximum concentration (Tmax) Up to 26 monthsArea under the curve from time zero to 24 hours (AUC0-24) Up to 26 monthsOverall Response Rate (ORR) Up to 26 monthsDuration of Response (DOR) Up to 26 monthsClinical Benefit Rate (CBR) Up to 26 months

[0225] Dosage forms of Compound 1 include solid dosage forms of the active agent at 0.5 mg, 1.0 mg, 10 mg, and 20 mg.

[0226] Based upon the preclinical data collected to date, it is expected that the study may show that Compound 1 is safe and tolerable in the indicated patient populations, and is efficacious when administered as a monotherapy and / or in combination with the exemplary anti-estrogens, fulvestrant or palazestrant.Page 59 of 6913238167vlAttorney Docket No. 2012034-0398EXAMPLE 9In Vitro Study of a KAT6 Inhibitor Compound to Inhibit Proliferation in a Panel of + (HGSOC) Cell Lines

[0227] Inhibition of cell proliferation by Compound 1 in six different HGSOC cell lines was investigated. The cell lines used are provided in Table 14 below, along with their genomic profiles. The human ovarian cancer cell lines used in the assays have genomic profiles characteristic of HGSOC, including TP53 mutations. A TP53 mutation is a change in the tumor suppressor gene that normally expresses a protein, tumor protein p53, that prevents cancer by controlling cell growth and repair. Somatic mutations in the TP53 gene are one of the most frequent alterations in human cancers and are present in nearly all HGSOC tumors (96%) (Olivier, M., el al., Cold Spring Harb Perspect Biol. 2010 Jan; 2(1). The Cancer Genome Atlas Research Network, Nature. 2011 Jun 29;474(7353).

[0228] Optimized cell densities were plated in 96-well plates and incubated overnight in complete media appropriate for each cell line. Cells were treated with serial dilutions of Compound 1; treatment duration ranged between 7 and 21 days. Cell proliferation was assessed using either Cell Titer Gio® 2.0 or CYQUANT™ reagents. Growth was normalized to T=0.

[0229] Cellular and genomic characteristics of the different ovarian cancer cell lines used are provided in the table below; provided in column 2 is the inhibition of cell proliferation by Compound 1.Table 14.Cell Line Compound Log2TPM TP53 Other Platinum status 1 (KAT6A) status lesions at derivation GI50 (nM)OAW28 9.0 6.1 Deletion KAT6A RefractoryampNIH: OVCAR3 231 4.0 SNV CCNE1 Resistant(GoF) ampPage 60 of 6913238167vlAttorney Docket No. 2012034-0398UWB 1.289 71.6 2.6 Deletion BRCA1- / - Resistant (BRCA1- null)PEO1 n / a 2.1 SNV BRCA2- / - SensitiveBRCA nullPEO4 0.6 1.8 SNV ResistantCOV413A 33.1 3.2 SNV Untreated

[0230] In reference to Table 14, LOG2TPM (transcripts per million) is a measure of gene expression of KAT6A; TP53 (tumor protein 53) status indicates the status of deletions or mutations in TP53, where deletion indicates inactivation, SNV indicates a single nucleotide variant, GoF indicates a gain of function mutation, KAT6A amp indicates amplification of KAT6A, CCNE1 (Cyclin El) amp indicates amplification of CCNE1, BRCA1- / - means that the BRCA1 gene is non-functional (deficient), BRCA2- / - means that the BRCA2 gene is non-functional (deficient). Regarding certain of the ovarian cell lines used in the study, UWB 1.289 was derived from a germline BRCA1 mutant tumor, homologous recombination deficiency (HRD) is partially restored when BRCA1 is overexpressed. Cell lines PEO1 and PEO4 were derived from the same patient before and after the onset of platinum resistance.

[0231] The cell proliferation results in Table 14 illustrate that Compound 1 potently inhibits proliferation of multiple high grade serous ovarian cancer cell lines in vitro, with nanomolar potencies.

[0232] Additionally, based on the cell proliferation results of Compound 1 on UWB 1.289 ovarian cancer cells (BRCA1-null and +BRCA1) using the PARP inhibitor, olaparib, as a comparator, where the activity of PARP inhibitor compounds is dependent upon BRCA status, Compound 1 activity in ovarian cancer was shown to be independent of BRCA status. See FIGs.15A (olaparib) and 15B (Compound 1).

[0233] As noted above, ovarian cancer cell lines PEO1 and PEO4 were derived from the same patient before and after the onset of platinum resistance. Cell proliferation results for carboplatin and Compound 1 are shown in FIGs. 16A and 16B, respectively, plotted as percent relative cellPage 61 of 6913238167vlAttorney Docket No. 2012034-0398proliferation versus concentration (Log (M) concentration). FIG. 16B illustrates a potent antiproliferative effect of Compound 1 on platinum-resistant PEO4 ovarian cancer cells harboring a BRCA2 reversion mutation, in comparison to the minimal anti-proliferative effect of carboplatin on both cell lines up to a concentration of about -7 (log concentration). Compound 1, as a monotherapy, demonstrates activity in an in-vitro platinum resistant ovarian cancer model.EXAMPLE 10In Vitro Analysis: Combinations of a KAT6 Inhibitor Compound and Platinum Therapy or a PARP inhibitor in a Platinum-Sensitive Ovarian Cancer Cell Line

[0234] Combination Therapy: Optimized cell densities were plated in 96-well plates and incubated overnight in complete media appropriate for PEO1 and PEO4 ovarian cancer cell lines having the characteristics described in Example 9 above. Cells were treated with serial dilutions of Compound 1 in the presence of fixed doses of standard of care compounds, carboplatin, olaparib, palazestrant. or vehicle control. Treatment duration was 12-14 days. Cell proliferation was measured using Cell Titer Gio® 2.0 and synergy was assessed using the Zero Interaction Potency (ZIP) scoring model as previously described. Scores greater than 10 are indicative of a synergistic effect while scores less than 10 indicate antagonism. Intermediate values suggest an additive effect.

[0235] Synergy analysis was carried out as described above. Synergy plots for the doublet combinations of Compound 1 and each of carboplatin, olaparib, and palazestrant are provided in FIGs. 17A-C, respectively. The synergy analysis indicates that Compound 1 acts synergistically when combined with platinum therapy or with a PARP inhibitor in platinum- sensitive PEO1 cells.

[0236] The embodiments of the disclosure described herein are intended to be merely exemplary, numerous variations and modifications will be apparent to those skilled in the art. All such variations and modifications are intended to be within the scope of the present disclosure as defined in any appended claims.Page 62 of 6913238167vl

Claims

1. Attorney Docket No. 2012034-0398CLAIMS1. A method of treating a treating a disease, disorder, or condition by inhibiting lysine acetyltransferase 6A (KAT6A) and acetyltransferase 6B (KAT6B), the method comprising administering to a subject in need thereof an effective amount of Compound 1,Compound 1,or a pharmaceutically acceptable salt thereof.

2. The method of claim 1, wherein the disease, disorder, or condition is a cancer.

3. The method of claim 2, wherein the subject has a solid tumor derived from the cancer.

4. The method of claims 2 or 3, wherein the cancer is ovarian cancer, prostate cancer, nonsmall cell lung cancer (“NSCLC”).

5. The method of claim 4, wherein the cancer is ovarian cancer and the subject has a BRCA mutation.

6. The method of claim 4, wherein the cancer is ovarian cancer and the subject does not have a BRCA mutation.

7. The method of any one of claims 1-4, wherein the disease, disorder, or condition is prostate cancer.

8. The method of claim 7, wherein the prostate cancer is castration-resistant prostate cancer.

9. The method of any one of claims 1-4, wherein the disease, disorder, or condition is nonsmall cell lung cancer.

10. The method of any one of claims 1-3, wherein the disease, disorder, or condition is breast cancer, optionally wherein:Page 63 of 6913238167vlAttorney Docket No. 2012034-0398the breast cancer is ER- / HER2+ breast cancer;the breast cancer is triple negative breast cancer;the breast cancer is advanced or metastatic breast cancer;the breast cancer is ER+ / HER2+ breast cancer;the breast cancer is ESRlwt ER+ / HER2+ breast cancer; orthe breast cancer is an ESRI mutant breast cancer.

11. The method of claim 10, wherein the breast cancer is advanced or metastatic breast cancer.

12. The method of any one of claims 10-11, wherein the breast cancer is ER+ / HER2+ breast cancer.

13. The method of any one of claims 10-11, wherein the breast cancer is ESRlwt ER+ / HER2+ breast cancer.

14. The method of any one of claims 10-11, wherein the breast cancer is an ESRI mutant breast cancer.

15. The method of claim 14, wherein the ESRI mutant breast cancer is ER+ / HER2-.

16. The method of any one of claims 1-6, wherein the disease, disorder, or condition is ovarian cancer.

17. The method of claim 16, wherein the ovarian cancer is high grade serous ovarian cancer.

18. The method of any one of claims 16-17. wherein the ovarian cancer is platinum resistant.

19. The method of any one of claims 1-18, wherein over the course of treatment, the volume of the tumor size decreases from at least about 50% to about 150% of its size at baseline.Page 64 of 6913238167vlAttorney Docket No. 2012034-039820. The method of any one of claims 1-19, wherein the subject is administered a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

21. The method of claim 20, wherein the pharmaceutical composition is a solid dosage form.

22. The method of claim 21, wherein the solid dosage form is a tablet or capsule.

23. The method of any one of claims 1-22, wherein Compound 1 is administered orally.

24. The method of any one of claims 1-23, wherein Compound 1 is administered once every other day, once per day, twice per day, once per week, twice per week, or once per month.

25. The method of any one of claims 1-24, wherein Compound 1 is administered in an amount that is from about 0.5 mg to about 1000 mg per dose.

26. The method of any one of claims 1-25, wherein Compound 1 is administered in an amount that is from about 0.5 mg to about 100 mg per dose.

27. The method of any one of claims 1-26, wherein Compound 1 is administered in an amount that is from about 0.5 mg to about 50 mg per dose.

28. The method of any one of claims 1-27, wherein Compound 1 is administered in an amount that is from about 0.5 mg to about 25 mg per dose.

29. The method of any one of claims 1-28, wherein the subject has previously received an alternative anti-cancer treatment.

30. The method of claim 29, wherein the alternative anti-cancer treatment is selected from treatment with an androgen receptor antagonist, a tyrosine kinase inhibitor, an mTOR inhibitor, a PARP inhibitor, a taxoid agent, an antineoplastic agent, or a combination of any one or more of the foregoing.Page 65 of 6913238167vlAttorney Docket No. 2012034-039831. The method of any one of claims 1 -30, further comprising administering to the subject a second therapeutic agent.

32. The method of claim 31, wherein the second therapeutic agent is a selective estrogen receptor modulator (SERM), a selective estrogen receptor degrader (SERD), a CDK4 / 6 inhibitor, a CDK4-selective inhibitor, a PI3 kinase inhibitor, an aromatase inhibitor, an mTOR inhibitor, an antibody to or inhibitor of PD-1, PD-L1 or CTLA-4, an antibody to or inhibitor of EGFR, PDGFR, or IGFR, a USP1 inhibitor, an AKT inhibitor, a PARP inhibitor, a taxoid agent, or antineoplastic agent.

33. The method of claims 31 or 32, wherein the disease, disorder, or condition is prostate cancer or non- small cell lung cancer, and the second therapeutic agent is docetaxel.

34. The method of claims 31 or 32, wherein the disease, disorder, or condition is advanced breast cancer or metastatic breast cancer, and the second therapeutic agent is fulvestrant.

35. The method of claims 31 or 32, wherein the disease, disorder, or condition is advanced breast cancer or metastatic breast cancer, and the second therapeutic agent is palazestrant.

36. The method of claims 31 or 32, wherein the disease, disorder, or condition is advanced breast cancer or metastatic breast cancer, and the second therapeutic agent is ribociclib.

37. The method of claims 31 or 32, wherein the disease, disorder, or condition is advanced breast cancer or metastatic breast cancer, and the second therapeutic agent is palbociclib.

38. The method of claims 31 or 32, wherein the disease, disorder, or condition is ovarian cancer, and the second therapeutic agent is a platinum agent.

39. The method of claims 31 or 32, wherein the disease, disorder, or condition is ovarian cancer, and the second therapeutic agent is a PARP inhibitor.Page 66 of 6913238167vlAttorney Docket No. 2012034-039840. The method of any one of claims 31 -39, further comprising administering to the subject a third therapeutic agent that is different from the second therapeutic agent.

41. The method of claim 40, wherein the third therapeutic agent is a selective estrogen receptor modulator (SERM), a selective estrogen receptor degrader (SERD), a CDK4 / 6 inhibitor, a CDK4-selective inhibitor, a PI3 kinase inhibitor, an aromatase inhibitor, an mTOR inhibitor, an antibody to or inhibitor of PD-1, PD-L1 or CTLA-4, an antibody to or inhibitor of EGFR, PDGFR, or IGFR, a USP1 inhibitor, an AKT inhibitor, a PARP inhibitor, a taxoid agent, an antineoplastic agent, or a platinum agent.

42. The method of claims 40 or 41, wherein the third therapeutic agent is docetaxel.

43. The method of claims 40 or 41, wherein the third therapeutic agent is fulvestrant.

44. The method of claims 40 or 41, wherein the third therapeutic agent is palazestrant.

45. The method of claims 40 or 41, wherein the third therapeutic agent is ribociclib.

46. The method of claims 40 or 41, wherein the third therapeutic agent is palbociclib.

47. The method of claims 40 or 41, wherein the third therapeutic agent is a platinum agent.

48. The method of of claims 40 or 41, wherein the third therapeutic agent is a PARP inhibitor.

49. A method of treating a solid cancer comprising administering to a subject in need thereof an effective amount of Compound 1Compound 1or a pharmaceutically acceptable salt thereof, wherein the cancer is ovarian cancer, prostate cancer, or non-small cell lung cancer.Page 67 of 6913238167vlAttorney Docket No. 2012034-039850. A method of inhibiting tumor growth in a subject in need thereof, wherein the tumor is an ovarian cancer tumor, a prostate cancer tumor, or a non-small cell lung cancer tumor, comprising administering to the subject an effective amount of Compound 1,Compound 1or a pharmaceutically acceptable salt thereof,.

51. A method of treating a platinum-resistant ovarian cancer, comprising administering to a subject in need thereof an effective amount of Compound 1,Compound 1or a pharmaceutically acceptable salt thereof.

52. A method of treating a platinum-sensitive ovarian cancer, comprising administering to a subject in need thereof an effective amount of Compound 1,Compound 1or a pharmaceutically acceptable salt thereof, a PARP inhibitor, and / or a platinum agent.Page 68 of 6913238167vl

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