Methods of improving glycemic control with a menin inhibitor

Abstract

Provided herein are methods of improving glycemic control in an individual, wherein the methods comprise administering a menin inhibitor, such as ziftomenib or a pharmaceutically acceptable form thereof, to the individual.

Description

WSGR Reference No.47535-754.601 METHODS OF IMPROVING GLYCEMIC CONTROL WITH A MENIN INHIBITOR CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No.63 / 659,748, filed June 13, 2024, U.S. Provisional Application No. 63 / 649,176, filed May 17, 2024, and U.S. Provisional Application No. 63 / 625,036 filed January 25, 2024, each of which is incorporated herein by reference in their entirety. FIELD

[0002] Provided herein are methods of treating diabetes with a menin inhibitor, such as ziftomenib. Pharmaceutical compositions, kits, and related products are also embodied within this disclosure. BACKGROUND

[0003] Diabetes mellitus, commonly referred to as diabetes, is a disease in which the body does not produce or properly respond to insulin, a hormone that is needed to convert sugar, starches, and other food into energy. The hallmark indicator of diabetes is the presence of high blood sugar levels. Generally, diabetes is described by its two main forms: type 1 and type 2 diabetes. As of 2021, approximately 38.4 million people in the United States and 537 million people worldwide (roughly 10-11% of the population) have diabetes, and this number is predicted to increase to 643 million by 2030 and 783 million by 2045. Of all diabetes cases, type 1 diabetes accounts for approximately 5% to 10%, and type 2 diabetes about 90%.

[0004] Type 1 diabetes, which is typically diagnosed in children and young adults, is an autoimmune disease in which the body is unable to produce insulin. The underlying mechanism involves autoimmune destruction of the insulin-producing beta cells in the pancreas, causing the pancreas to produce either very little insulin or none at all. As a consequence, the lack of insulin results in high sugar levels in the blood.

[0005] Type 2 diabetes (T2D) (or type 2 diabetes mellitus) is typically diagnosed in middle- aged and older adults and is one of the most common metabolic disorders. It is caused by two parallel, progressive disease mechanisms within the body—the inability of insulin-sensitive tissues to respond appropriately to insulin (insulin resistance) and the defective insulin secretion by pancreatic β-cells (insulin insufficiency). As a result of these mechanisms, elevated sugar levels are maintained in the bloodstream, leading to a range of systemic complications. A range of physiological changes occur during the progression from prediabetes to type 2 diabetes,WSGR Reference No.47535-754.601 including increases in postprandial glucose concentration, fasting glucose concentration, and insulin secretion, an increase followed by a decrease in insulin secretion, and a drop in beta-cell function; as the condition progresses patients begin to experience macrovascular complications and eventually, microvascular complications Piya et al. Br. J. Clin. Pharmacol.2010, 70(5), 631- 644). Insulin resistance is typically measured by HOMA-IR; insulin secretion is measured by blood insulin and c-peptide concentrations; postprandial glucose is typically measured through an oral glucose tolerance test (OGTT); and fasting glucose is evaluated by measuring fasting blood glucose levels.

[0006] One of the central pathogeneses of both Type-1 and Type-2 diabetes is the failure of pancreatic β-cells. Type-1 diabetes is caused by autoimmune destruction of pancreatic β-cell mass by unknown mechanisms, and Type-2 diabetes is associated with decreased insulin secretion due to the β-cell exhaustion. A major focus in diabetes research is to increase / restore β-cell function with therapies such as GLP-1 receptor agonists, such as GLP-1R agonist peptides (GLP-1 peptides, e.g. Ozempic), or sulfonylurea. However, these therapies may be effective only if there are still enough functional β-cells in pancreatic islets. However, T1D patients and late stage T2D patients often do not have enough functional β-cell mass. Preventing or restoring the loss of β-cell mass by enhancing the β-cell proliferation and β-cell mass expansion could provide meaningful clinical benefit, but there is no established method to stimulate proliferation β-cells in human islets without affecting other cell types or organs. Although stimuli such as mitogens, growth factors, GLP-1, and many molecules may increase rat and mouse β-cell proliferation and β-cell mass expansion, these agents have little to no effect in human β-cells. DYRK1 inhibitors, including harmine, may stimulate human β-cell proliferation efficiently, but are non-specific and cause proliferation of α-cells, acinar cells, and d-cells in islets and in other organs such as small intestine, thereby increasing the risk of inducing oncologic complications.

[0007] There is currently no cure for diabetes, but it can be treated and controlled, in particular through control of blood glucose. Nevertheless, current treatments for diabetes suffer from a number of significant drawbacks, including failure to manage blood glucose levels and other comorbidities (such as hypertension, dyslipidemia, kidney disease, peripheral neuropathy, increased risk of cardiovascular events, e.g., myocardial infarction and stroke) adequately, inconvenience in continuously monitoring blood sugar levels and administering treatments, limitations in maintaining long term efficacy, increased risk of side effects, and difficulties in maintaining patient compliance. In addition, although insulin resistance is the root cause of T2D, very few drugs improve insulin sensitivity safely and effectively, especially in later-stage T2D patients.WSGR Reference No.47535-754.601

[0008] The mixed-lineage leukemia (MLL) protein is a histone methyltransferase critical for the epigenetic regulation of gene transcription. The menin protein, which is encoded by the Multiple Endocrine Neoplasia (MEN) gene, is a ubiquitously expressed nuclear protein that engages in interactions with DNA processing and repair proteins, chromatin modifying proteins and numerous transcription factors (Agarwal et al., Horm. Metab. Res.2005, 37(6), 369-374). Menin is an epigenetic scaffold protein known to regulate pathogenic gene expression in several cell types. Genetic menin loss (MEN1 Syndrome) is associated with insulinemia due to upregulated pancreatic β-cell proliferation. The association of menin with MLL promotes trimethylation of histone H3 on lysine 4. This association has been shown to maintain the expression of p27Kip1 and p18INK4C and impair islet proliferation. Menin is thought to be involved in the proliferation of pancreatic β-cells and thus has been considered as a viable target to treat defective insulin secretion (Karnik et al., Proc. Natl. Acad. Sci.2005, 102(41), 14659- 14664; Li et al., Cell Reports 2023, 42, 111904). However, no validated menin inhibitors have been tested thoroughly in T2D animal studies and the effects on insulin resistance have not been investigated.

[0009] GLP-1R agonists, such as semaglutide and tirzepatide, have been studied for reducing excess body weight and maintaining weight reduction in patients with obesity or who are overweight and have at least one weight-related comorbid condition, and semaglutide is approved for these indications. While these agents primarily act by reducing fat mass, side effects of muscle atrophy and loss of lean muscle mass are of concern; studies showed that semaglutide and tirzepatide caused muscle loss of at least 10%, which accounted for 40% of weight loss in the semaglutide group (The Semaglutide Treatment Effect in People with Obesity, STEP-1 trial; Neeland et al., Diabetes Obes. Metab.2024, 26(Suppl.4), 16-27; Wilding et al., N. Engl. J. Med.2021, 384, 989-1002). Consequently, patients taking semaglutide are encouraged to exercise in order mitigate muscle loss. Although research is ongoing into alternative therapeutic regimens, such as combination therapies (e.g., semaglutide with a long-acting amylin analogue such as cagrilintide) or agents with different mechanisms of action (e.g., a monoclonal antibody to activin type II receptors, such as bimagrumab, in combination with semaglutide; Eli Lilly Press Release, July 14, 2023), that might drive substantial fat loss while maintaining or increasing lean muscle mass, no treatments have been approved for combating the muscle loss caused by GLP-1R agonists. There is a need for therapeutic alternatives or combinations for treating obesity or related conditions that induce weight loss without the muscle atrophy associated with GLP-1R agonists.WSGR Reference No.47535-754.601 SUMMARY

[0010] There remains considerable need for alternative therapeutics for treatment of diabetes, particularly for effective therapies that act through different mechanisms of action than existing therapies, and that do not cause significant side effects, toxicity, or drug-drug interactions (see Fumagalli et al., Molecules 202025(8), 1987). Further, there is also a need for potential therapies that target β-cells function specifically. Zucker Diabetic Fatty rats were used to assess the antidiabetic activity of ziftomenib dosed orally once daily for 27 days. Ziftomenib treatment was well tolerated and rapidly reduced fasting blood glucose (FBG) levels, with most animals normalizing FBG levels within two weeks. Ziftomenib also progressively reduced %HbA1c by an average of 1.49pp by week 4. Oral glucose tolerance tests demonstrated that ziftomenib- treated animals achieved significantly improved postprandial glucose control. Ziftomenib induced a reduction in HOMA-IR within a week, suggesting that one of the effects of menin inhibition is acute sensitization of the animals to insulin. In addition, fasting insulin and c- peptide concentrations demonstrated that ziftomenib significantly stimulated insulin production at week 3-4. These observations suggest that pharmacological targeting of menin is a viable option to treat both insulin resistance and insulin insufficiency, the two main pathological features of T2DM.

[0011] In some embodiments, provided herein is a method of improving glycemic control in an individual comprising administering to the individual a menin inhibitor. In some embodiments, provided herein is a method of reducing %HbA1c in an individual with elevated %HbA1c comprising administering to the individual a menin inhibitor. In some embodiments, provided herein is a method of reducing body weight in an individual comprising administering to the individual a menin inhibitor. In some embodiments, provided herein is a method of reducing fasting blood glucose in an individual comprising administering to the individual a menin inhibitor. In some embodiments, provided herein is a method of improving postprandial glucose control in an individual comprising administering to the individual a menin inhibitor. In some embodiments, provided herein is a method of improving insulin sensitivity in an individual comprising administering to the individual a menin inhibitor. In some embodiments, provided herein is a method of increasing fasting plasma insulin concentration in an individual comprising administering to the individual a menin inhibitor.

[0012] There is also a need for alternative therapeutics that can be used in combination with GLP-1R agonists in order to enhance the effects of the GLP1-R agonist in treating diabetes and / or inducing weight loss and / or to mitigate muscle atrophy and lean muscle mass loss characteristic of GLP-1R agonist therapies. As described herein, menin inhibitors such as ziftomenib can reduce blood glucose levels and enhance β-cell mass, thereby enhancing theWSGR Reference No.47535-754.601 positive features of GLP-1R agonist therapy and / or, importantly, may mitigate muscle atrophy caused by GLP-1R agonists and may induce muscle gain. In some embodiments, the methods described herein comprise administering to an individual a menin inhibitor and a GLP-1R agonist. In some embodiments, the combination produces less muscle atrophy or lean muscle mass loss than the GLP-1R agonist alone.

[0013] In some embodiments, the methods described herein comprise administering a menin inhibitor in combination with a PPAR agonist, such as rosiglitazone or pioglitazone, for the treatment of insulin resistance, as a combination with a menin inhibitor such as ziftomenib may improve insulin sensitivity, optionally by upregulating the PPAR pathway.

[0014] In some embodiments, the menin inhibitor is a compound of Formula (II-A) or (III-A), or a pharmaceutically acceptable form thereof. In some embodiments, the menin inhibitor is ziftomenib or a pharmaceutically acceptable form thereof. INCORPORATION BY REFERENCE

[0015] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. BRIEF DESCRIPTION OF THE DRAWINGS

[0016] FIG.1: Plot of 4 h fasting blood glucose (mmol / L) over time for dosing with vehicle, ziftomenib, semaglutide, and BMF-219 in ZDF rats.

[0017] FIG.2: Plot of Day 27 fasting blood glucose (mmol / L) for dosing with vehicle, ziftomenib, semaglutide, and BMF-219 in ZDF rats.

[0018] FIG.3: Plot of 4 h fasting blood glucose (mmol / L) over time for individual ZDF rats treated with ziftomenib.

[0019] FIG.4: Plot of 4 h fasting blood glucose (mmol / L) over time for individual ZDF rats treated with BMF-219.

[0020] FIG.5: Plot of 24 h water intake (g) over time for ZDF rats treated with vehicle, ziftomenib, semaglutide, or BMF-219.

[0021] FIG.6: Plot of 24 h food intake (g) over time for ZDF rats treated with vehicle, ziftomenib, semaglutide, or BMF-219.

[0022] FIG.7: Plot of body weight (average, g) over time for ZDF rats treated with vehicle, ziftomenib, semaglutide, or BMF-219.

[0023] FIG.8: Plot of %HbA1c over time for ZDF rats treated with vehicle, ziftomenib, semaglutide, or BMF-219.WSGR Reference No.47535-754.601

[0024] FIG.9: Plot of results of blood glucose (mmol / L) over time from an oral glucose tolerance test (OGTT) performed on Day 27 for ZDF rats treated with vehicle, ziftomenib, semaglutide, or BMF-219.

[0025] FIG.10: Plot of results of blood glucose AUC measurements (mmol / L-min) from OGTT performed on Day 27 for ZDF rats treated with vehicle, ziftomenib, semaglutide, or BMF-219.

[0026] FIG.11: Plot of calculated HOMA-IR values obtained over time for ZDF rats treated with vehicle, ziftomenib, semaglutide, or BMF-219.

[0027] FIG.12A: Plot of 4 h fasting insulin concentrations (ng / mL) obtained over time for ZDF rats treated with vehicle, ziftomenib, semaglutide, or BMF-219.

[0028] FIG.12B: Plot of calculated HOMA-B values obtained over time for ZDF rats treated with vehicle, ziftomenib, semaglutide, or BMF-219.

[0029] FIG.13: Plot of c-peptide concentrations (pmol / L) obtained on Day 27 for ZDF rats treated with vehicle, ziftomenib, semaglutide, or BMF-219.

[0030] FIG.14: Plot of ziftomenib plasma concentrations (average; ng / mL) for ZDF rats treated with ziftomenib (100 mg / kg or 200 mg / kg).

[0031] FIGs.15A-C: Plots of 4-hour fasting blood glucose (mmol / L) over time (FIG.15A), 4-hour fasting insulin levels (mg / mL) over time (FIG.15B), and c-peptide levels at Day 56 (FIG.15C), for db / db mice treated for 28 days with vehicle, ziftomenib, semaglutide, and BMF- 219 and observed during a 28-day wash-out period.

[0032] FIG.16: Plot of 4 h fasting blood glucose (mmol / L) over time for db / db mice treated with vehicle, ziftomenib, bleximenib, or semaglutide for 35 days.

[0033] FIG.17A-B: Bar graphs showing cell counts for Donor 1 MT samples treated with vehicle, ziftomenib (100 nM or 500 nM), or harmine (10 µM) under standard or glucotoxic conditions for proliferating β-cells (FIG.17A) and proliferating non-β-cells (FIG.17B). Unpaired t-test between each condition and its respective solvent, *p < 0.05, **p < 0.01, ***p < 0.001. Unpaired t-test between each condition and its respective solvent. Unpaired t-test of GTX DMSO control vs. STD DMSO control #p < 0.05, ##p < 0.01, ###p < 0.001.

[0034] FIG.18A-C: Bar graphs showing cell counts for Donor 2 MT samples treated with vehicle, ziftomenib (100 nM or 500 nM), or harmine (10 µM) under standard or glucotoxic conditions for proliferating β-cells (FIG.18A), proliferating non-β-cells (FIG.18B), and total β-cells (FIG.18C). Unpaired t-test between each condition and its respective solvent, *p < 0.05, **p < 0.01, ***p < 0.001.

[0035] FIG.19A-B: Bar graphs showing cell counts for Donor 3 MT samples treated with vehicle ziftomenib (33 nM or 100 nM), or harmine (10 µM) under standard or glucotoxicWSGR Reference No.47535-754.601 conditions for proliferating β-cells (FIG.19A) and total β-cells (FIG.19B). Unpaired t-test between each condition and its respective solvent, *p < 0.05, **p < 0.01, ***p < 0.001.

[0036] FIG.20A-C: Plots of 4 h fasting blood glucose (mmol / L) (FIG.20A) and fasting insulin concentration (ng / mL) (FIG.20B) for Days 0 to 42 dosing with vehicle and ziftomenib (25, 50, or 100 mg / kg), and for fasting blood glucose (mmol / L) (FIG.20C) during a two-week washout period, in a ZDF rat model of advanced disease.

[0037] FIG.21: Plot of the percentage of insulin-positive areas among total areas analyzed in pancreatic tail samples obtained from ZDF rats treated for 42 days with vehicle or ziftomenib and compared to pancreatic tail samples from untreated Zucker-lean rats.

[0038] FIG.22A-B: Plots of body fat percentage (FIG.22A) and body lean mass percentage (FIG.22B) for ZDF rats after treatment for 27 days with vehicle, ziftomenib, or revumenib, as measured by Echo-MRI.

[0039] FIG.23A-B: Plots of body fat (g) (FIG.23A) and body lean mass (g) (FIG.23B), for db / db mice after treatment for 26 days with vehicle, ziftomenib, or revumenib, as measured by Echo-MRI. DETAILED DESCRIPTION

[0040] An orally available menin inhibitor ziftomenib sensitized T2D model rats (ZDF male rats; Zucker diabetic fatty male rats) to insulin rapidly and normalized their fasting blood glucose (FBG) levels within a week. The improvement continued over the course of 4 weeks of QD dosing, resulting in the normalization FBG in most of the animals and a robust reduction of %HbA1c (mean, approximately -1.5 percentage points). In addition, ziftomenib stimulated the insulin production in the animals after 3-4 weeks of dosing. These results suggest that the single agent ziftomenib can address both of the two fundamental pathophysiological mechanisms underlying T2D—insulin resistance and insulin insufficiency. Ziftomenib was well-tolerated. Liver histopathology did not indicate hepatotoxicity, suggesting an encouraging safety profile for use of a menin inhibitor to treat diabetes, or specifically T2D. In some embodiments, administration of ziftomenib according to the methods described herein does not induce hepatotoxicity.

[0041] Although BMF-219 induced a reduction in FBG, ziftomenib showed a significantly superior efficacy throughout the study. Notably, BMF-219 did not produce a significant reduction in %HbA1c or an increase in insulin production. Continuous decline in body weight and extremely low food intake in BMF-219-treated animals suggested that observed reductions in FBG and HOMA-IR may have been due to the significant reduction in food consumption inWSGR Reference No.47535-754.601 these animals. In contrast, food and water intake of ziftomenib-treated animals remained at the normal level throughout dosing.

[0042] In some embodiments, provided herein is a method of improving glycemic control in an individual comprising administering to the individual a menin inhibitor. In some embodiments, the menin inhibitor is administered in an effective amount. In some embodiments, the administering reduces %HbA1c in the individual. In some embodiments, the individual has an elevated %HbA1c prior to the administering. Menin Inhibitors

[0043] In some embodiments, the menin inhibitor is a menin inhibitor described in any of U.S. Patent Nos.8,993,552, 9,216,993, 9,505,781, 9,505,782, 10,077,271, 10,160,769, 10,174,041, 10,246,464, 10,588,907, 10,752,639, 10,781,218, 11,542,248, 11,555,041, 11,649,251, 11,673,898, or RE49,687, each of which disclosure is incorporated by reference herein.

[0044] In some embodiments of the method described herein, the menin inhibitor is a compound of Formula (I-A):or a pharmaceutically acceptable form thereof, wherein: (a) H is selected from C5-12 carbocycle and 5- to 12-membered heterocycle, each of which is optionally substituted with one or more R50; A is selected from bond, C3-12carbocycle, and 3- to 12-membered heterocycle; B is selected from C3-12 carbocycle and 3- to 12-membered heterocycle; and C is 3- to 12-membered heterocycle; or (b) H is selected from C3-12carbocycle and 3- to 12-membered heterocycle;each of Z1, Z2, Z3, and Z4is independently selected from -C(RA1)(RA2)-, -C(RA1)(RA2)- C(RA1)(RA2)-, -C(O)-, and -C(RA1)(RA2)-C(O)-, wherein no more than one of Z1, Z2, Z3, and Z4is -C(O)- or -C(RA1)(RA2)-C(O)-; RA1is, at each occurrence, independently selected from hydrogen and R50; RA2is, at each occurrence, independently selected from hydrogen and R50;WSGR Reference No.47535-754.601 each of Z5and Z6is independently selected from -C(H)- and -N-; B is selected from C3-12carbocycle and 3- to 12-membered heterocycle; and C is selected from bond, C3-12carbocycle, and 3- to 12-membered heterocycle; L1, L2, and L3are each independently selected from bond, -O-, -S-, -N(R51)-, -N(R51)CH2-, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)N(R51)-, -C(O)N(R51)C(O)-, -C(O)N(R51)C(O)N(R51)-, -N(R51)C(O)-, -N(R51)C(O)N(R51)-, -N(R51)C(O)O-, -OC(O)N(R51)-, -C(NR51)-, -N(R51)C(NR51)-, -C(NR51)N(R51)-, -N(R51)C(NR51)N(R51)-, -S(O)2-, -OS(O)-, -S(O)O-, -S(O)-, -OS(O)2-, -S(O)2O-, -N(R51)S(O)2-, -S(O)2N(R51)-, -N(R51)S(O)-, -S(O)N(R51)-, -N(R51)S(O)2N(R51)-, and -N(R51)S(O)N(R51)-; and alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, and heteroalkynylene, wherein each of the alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, and heteroalkynylene is optionally substituted with one or more R50, wherein two R50groups attached to the same atom or different atoms of any one of L1, L2, or L3can together optionally form a bridge or ring; RA, RB, and RCare each independently selected at each occurrence from R50; or two RAgroups, two RBgroups, or two RCgroups attached to the same atom or different atoms can together optionally form a bridge or ring; m, n, and p are each independently an integer from 0 to 6; R50is independently selected at each occurrence from: halogen, -NO2, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=O)R52, -S(=O)2R52, -S(=O)2N(R52)2, -S(=O)2NR53R54, -NR52S(=O)2R52, -NR52S(=O)2N(R52)2, -NR52S(=O)2NR53R54, -C(O)R52, -C(O)OR52, -OC(O)R52, -OC(O)OR52, -OC(O)N(R52)2, -OC(O)NR53R54, -NR52C(O)R52, -NR52C(O)OR52, -NR52C(O)N(R52)2, -NR52C(O)NR53R54, -C(O)N(R52)2, -C(O)NR53R54, -P(O)(OR52)2, - P(O)(R52)2, -P(O)(OR52)(R52), -P(O)(NR52)(R52), -NR52P(O)(R52), -P(O)(NR52)(OR52), and -P(O)(NR52)2; or two R50groups attached to the same atom taken together form =O, =S, or =N(R52); C1-10 alkyl, C2-10 alkenyl, and C2-10 alkynyl, each of which is optionally substituted at each occurrence with one or more substituents independently selected from halogen, -NO2, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=O)R52, -S(=O)2R52, -S(=O)2N(R52)2, -S(=O)2NR53R54, -NR52S(=O)2R52, -NR52S(=O)2N(R52)2, -NR52S(=O)2NR53R54, -C(O)R52, -C(O)OR52, -OC(O)R52, -OC(O)OR52, -OC(O)N(R52)2, -OC(O)NR53R54, -NR52C(O)R52, -NR52C(O)OR52, -NR52C(O)N(R52)2, -NR52C(O)NR53R54, -C(O)N(R52)2, -C(O)NR53R54, -P(O)(OR52)2, - P(O)(R52)2, -P(O)(OR52)(R52), -P(O)(NR52)(R52), -NR52P(O)(R52),WSGR Reference No.47535-754.601 -P(O)(NR52)(OR52), -P(O)(NR52)2, =O, =S, =N(R52), C3-12 carbocycle, and 3- to 12- membered heterocycle; and C3-12carbocycle and 3- to 12-membered heterocycle, wherein each C3-12carbocycle and 3- to 12-membered heterocycle in R50is optionally substituted with one or more substituents independently selected from halogen, -NO2, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=O)R52, -S(=O)2R52, -S(=O)2N(R52)2, -S(=O)2NR53R54, -NR52S(=O)2R52, -NR52S(=O)2N(R52)2, -NR52S(=O)2NR53R54, -C(O)R52, -C(O)OR52, -OC(O)R52, -OC(O)OR52, -OC(O)N(R52)2, -OC(O)NR53R54, -NR52C(O)R52, -NR52C(O)OR52, -NR52C(O)N(R52)2, -NR52C(O)NR53R54, -C(O)N(R52)2, -C(O)NR53R54, -P(O)(OR52)2, -P(O)(R52)2, -P(O)(OR52)(R52), -P(O)(NR52)(R52), -NR52P(O)(R52), -P(O)(NR52)(OR52), -P(O)(NR52)2, =O, =S, =N(R52), C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6alkynyl; R51is independently selected at each occurrence from: hydrogen, -C(O)R52, -C(O)OR52, -C(O)N(R52)2, -C(O)NR53R54; C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is optionally substituted at each occurrence with one or more substituents independently selected from halogen, -NO2, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=O)R52, -S(=O)2R52, -S(=O)2N(R52)2, -S(=O)2NR53R54, -NR52S(=O)2R52, -NR52S(=O)2N(R52)2, -NR52S(=O)2NR53R54, -C(O)R52, -C(O)OR52, -OC(O)R52, -OC(O)OR52, -OC(O)N(R52)2, -OC(O)NR53R54, -NR52C(O)R52, -NR52C(O)OR52, -NR52C(O)N(R52)2, -NR52C(O)NR53R54, -C(O)N(R52)2, -C(O)NR53R54, -P(O)(OR52)2, - P(O)(R52)2, -P(O)(OR52)(R52), -P(O)(NR52)(R52), -NR52P(O)(R52), -P(O)(NR52)(OR52), -P(O)(NR52)2, =O, =S, =N(R52), C3-12carbocycle, and 3- to 12- membered heterocycle; and C3-12 carbocycle and 3- to 12-membered heterocycle, wherein each C3-12carbocycle and 3- to 12-membered heterocycle in R51is optionally substituted with one or more substituents independently selected from halogen, -NO2, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=O)R52, -S(=O)2R52, -S(=O)2N(R52)2, -S(=O)2NR53R54, -NR52S(=O)2R52, -NR52S(=O)2N(R52)2, -NR52S(=O)2NR53R54, -C(O)R52, -C(O)OR52, -OC(O)R52, -OC(O)OR52, -OC(O)N(R52)2, -OC(O)NR53R54, -NR52C(O)R52, -NR52C(O)OR52, -NR52C(O)N(R52)2, -NR52C(O)NR53R54, -C(O)N(R52)2, -C(O)NR53R54, -P(O)(OR52)2, - P(O)(R52)2, -P(O)(OR52)(R52), -P(O)(NR52)(R52), -NR52P(O)(R52), -P(O)(NR52)(OR52), -P(O)(NR52)2, =O, =S, =N(R52), C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl;WSGR Reference No.47535-754.601 R52is independently selected at each occurrence from hydrogen; and C1-20 alkyl, C2-20 alkenyl, C2-20alkynyl, 1- to 6-membered heteroalkyl, C3-12carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted by halogen, -CN, -NO2, -NH2, -NHCH3, -NHCH2CH3, =O, -OH, -OCH3, -OCH2CH3, C3-12 carbocycle, or 3- to 6- membered heterocycle; R53and R54are taken together with the nitrogen atom to which they are attached to form a heterocycle; and R57is selected from: halogen, -NO2, -CN, -SR52, -NR53R54, -S(=O)R52, -S(=O)2R52, -S(=O)2N(R52)2, -S(=O)2NR53R54, -NR52S(=O)2R52, -NR52S(=O)2N(R52)2, -NR52S(=O)2NR53R54, -C(O)OR52, -OC(O)R52, -OC(O)OR52, -OC(O)N(R52)2, -OC(O)NR53R54, -NR52C(O)OR52, -NR52C(O)N(R52)2, -NR52C(O)NR53R54, -C(O)NH(C1-6alkyl), -C(O)NR53R54, -P(O)(OR52)2, -P(O)(R52)2, -P(O)(OR52)(R52), -P(O)(NR52)(R52), -NR52P(O)(R52), -P(O)(NR52)(OR52), -P(O)(NR52)2, =S, and =N(R52); and C1-10 alkyl, C2-10 alkenyl, and C2-10 alkynyl, each of which is substituted at each occurrence with one or more substituents independently selected from -NO2, -CN, -SR52, -N(R52)2, -NR53R54, -S(=O)R52, -S(=O)2R52, -S(=O)2N(R52)2, -S(=O)2NR53R54, -NR52S(=O)2R52, -NR52S(=O)2N(R52)2, -NR52S(=O)2NR53R54, -C(O)R52, -C(O)OR52, -OC(O)R52, -OC(O)OR52, -OC(O)N(R52)2, -OC(O)NR53R54, -NR52C(O)R52, -NR52C(O)OR52, -NR52C(O)N(R52)2, -NR52C(O)NR53R54, -P(O)(OR52)2, -P(O)(R52)2, - P(O)(OR52)(R52), -P(O)(NR52)(R52), -NR52P(O)(R52), -P(O)(NR52)(OR52), -P(O)(NR52)2, =S, and =N(R52).

[0045] In some embodiments, the menin inhibitor is a compound of Formula (I-B):or a pharmaceutically acceptable form thereof, wherein: H is selected from C5-12 carbocycle and 5- to 12-membered heterocycle, each of which is optionally substituted with one or more R50; A, B, and C are each independently selected from C3-12carbocycle and 3- to 12-membered heterocycle; L1and L2are each independently selected from bond, -O-, -S-, -N(R51)-, -N(R51)CH2-, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)N(R51)-, -C(O)N(R51)C(O)-,WSGR Reference No.47535-754.601 -C(O)N(R51)C(O)N(R51)-, -N(R51)C(O)-, -N(R51)C(O)N(R51)-, -N(R51)C(O)O-, -OC(O)N(R51)-, -C(NR51)-, -N(R51)C(NR51)-, -C(NR51)N(R51)-, -N(R51)C(NR51)N(R51)-, -S(O)2-, -OS(O)-, -S(O)O-, -S(O)-, -OS(O)2-, -S(O)2O-, -N(R51)S(O)2-, -S(O)2N(R51)-, -N(R51)S(O)-, -S(O)N(R51)-, -N(R51)S(O)2N(R51)-, and -N(R51)S(O)N(R51)-; and alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, and heteroalkynylene, wherein each of the alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, and heteroalkynylene is optionally substituted with one or more R50; L3is selected from alkylene, alkenylene, and alkynylene, each of which is substituted with one or more R56and optionally further substituted with one or more R50; RA, RB, and RCare each independently selected at each occurrence from R50; or two RAgroups, two RBgroups, or two RCgroups attached to the same atom or different atoms can together optionally form a bridge or ring; m, n, and p are each independently an integer from 0 to 6; R50is independently selected at each occurrence from: halogen, -NO2, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=O)R52, -S(=O)2R52, -S(=O)2N(R52)2, -S(=O)2NR53R54, -NR52S(=O)2R52, -NR52S(=O)2N(R52)2, -NR52S(=O)2NR53R54, -C(O)R52, -C(O)OR52, -OC(O)R52, -OC(O)OR52, -OC(O)N(R52)2, -OC(O)NR53R54, -NR52C(O)R52, -NR52C(O)OR52, -NR52C(O)N(R52)2, -NR52C(O)NR53R54, -C(O)N(R52)2, -C(O)NR53R54, -P(O)(OR52)2, - P(O)(R52)2, -P(O)(OR52)(R52), -P(O)(NR52)(R52), -NR52P(O)(R52), -P(O)(NR52)(OR52), and -P(O)(NR52)2; or two R50groups attached to the same atom taken together form =O, =S, or =N(R52); C1-10alkyl, C2-10alkenyl, and C2-10alkynyl, each of which is optionally substituted at each occurrence with one or more substituents independently selected from halogen, -NO2, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=O)R52, -S(=O)2R52, -S(=O)2N(R52)2, -S(=O)2NR53R54, -NR52S(=O)2R52, -NR52S(=O)2N(R52)2, -NR52S(=O)2NR53R54, -C(O)R52, -C(O)OR52, -OC(O)R52, -OC(O)OR52, -OC(O)N(R52)2, -OC(O)NR53R54, -NR52C(O)R52, -NR52C(O)OR52, -NR52C(O)N(R52)2, -NR52C(O)NR53R54, -C(O)N(R52)2, -C(O)NR53R54, -P(O)(OR52)2, - P(O)(R52)2, -P(O)(OR52)(R52), -P(O)(NR52)(R52), -NR52P(O)(R52), -P(O)(NR52)(OR52), -P(O)(NR52)2, =O, =S, =N(R52), C3-12 carbocycle, and 3- to 12- membered heterocycle; and C3-12carbocycle and 3- to 12-membered heterocycle, wherein each C3-12 carbocycle and 3- to 12-membered heterocycle in R50is optionally substituted with one or more substituents independently selected from halogen,WSGR Reference No.47535-754.601 -NO2, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=O)R52, -S(=O)2R52, -S(=O)2N(R52)2, -S(=O)2NR53R54, -NR52S(=O)2R52, -NR52S(=O)2N(R52)2, -NR52S(=O)2NR53R54, -C(O)R52, -C(O)OR52, -OC(O)R52, -OC(O)OR52, -OC(O)N(R52)2, -OC(O)NR53R54, -NR52C(O)R52, -NR52C(O)OR52, -NR52C(O)N(R52)2, -NR52C(O)NR53R54, -C(O)N(R52)2, -C(O)NR53R54, -P(O)(OR52)2, - P(O)(R52)2, -P(O)(OR52)(R52), -P(O)(NR52)(R52), -NR52P(O)(R52), -P(O)(NR52)(OR52), -P(O)(NR52)2, =O, =S, =N(R52), C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl; R51is independently selected at each occurrence from: hydrogen, -C(O)R52, -C(O)OR52, -C(O)N(R52)2, -C(O)NR53R54; C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is optionally substituted at each occurrence with one or more substituents independently selected from halogen, -NO2, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=O)R52, -S(=O)2R52, -S(=O)2N(R52)2, -S(=O)2NR53R54, -NR52S(=O)2R52, -NR52S(=O)2N(R52)2, -NR52S(=O)2NR53R54, -C(O)R52, -C(O)OR52, -OC(O)R52, -OC(O)OR52, -OC(O)N(R52)2, -OC(O)NR53R54, -NR52C(O)R52, -NR52C(O)OR52, -NR52C(O)N(R52)2, -NR52C(O)NR53R54, -C(O)N(R52)2, -C(O)NR53R54, -P(O)(OR52)2, - P(O)(R52)2, -P(O)(OR52)(R52), -P(O)(NR52)(R52), -NR52P(O)(R52), -P(O)(NR52)(OR52), -P(O)(NR52)2, =O, =S, =N(R52), C3-12carbocycle, and 3- to 12- membered heterocycle; and C3-12 carbocycle and 3- to 12-membered heterocycle, wherein each C3-12carbocycle and 3- to 12-membered heterocycle in R51is optionally substituted with one or more substituents independently selected from halogen, -NO2, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=O)R52, -S(=O)2R52, -S(=O)2N(R52)2, -S(=O)2NR53R54, -NR52S(=O)2R52, -NR52S(=O)2N(R52)2, -NR52S(=O)2NR53R54, -C(O)R52, -C(O)OR52, -OC(O)R52, -OC(O)OR52, -OC(O)N(R52)2, -OC(O)NR53R54, -NR52C(O)R52, -NR52C(O)OR52, -NR52C(O)N(R52)2, -NR52C(O)NR53R54, -C(O)N(R52)2, -C(O)NR53R54, -P(O)(OR52)2, - P(O)(R52)2, -P(O)(OR52)(R52), -P(O)(NR52)(R52), -NR52P(O)(R52), -P(O)(NR52)(OR52), -P(O)(NR52)2, =O, =S, =N(R52), C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, and C2-6 alkynyl; R52is independently selected at each occurrence from hydrogen; and C1-20 alkyl, C2-20 alkenyl, C2-20alkynyl, 1- to 6-membered heteroalkyl, C3-12carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted by halogen, -CN, -NO2, -NH2, -NHCH3, -NHCH2CH3, =O, -OH, -OCH3, -OCH2CH3, C3-12 carbocycle, or 3- to 6-WSGR Reference No.47535-754.601 membered heterocycle; R53and R54are taken together with the nitrogen atom to which they are attached to form a heterocycle; R56is independently selected at each occurrence from: -NO2, -OR59, -SR52, -NR53R54, -S(=O)R52, -S(=O)2R52, -S(=O)2N(R52)2, -S(=O)2NR53R54, -NR52S(=O)2R52, -NR52S(=O)2N(R52)2, -NR52S(=O)2NR53R54, -C(O)R52, -C(O)OR52, -OC(O)R52, -OC(O)OR52, -OC(O)N(R52)2, -OC(O)NR53R54, -NR52C(O)R52, -NR52C(O)OR52, -NR52C(O)N(R52)2, -NR52C(O)NR53R54, -C(O)N(R52)2, -C(O)NR53R54, -P(O)(OR52)2, -P(O)(R52)2, -P(O)(OR52)(R52), -P(O)(NR52)(R52), -NR52P(O)(R52), -P(O)(NR52)(OR52), -P(O)(NR52)2, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle; or two R56groups attached to the same atom taken together form =O, =S, or =N(R52); wherein each C1-10alkyl, C2-10alkenyl, and C2-10alkynyl in R56is optionally substituted at each occurrence with one or more substituents independently selected from halogen, - NO2, -CN, -OR59, -SR52, -N(R52)2, -NR53R54, -S(=O)R52, -S(=O)2R52, -S(=O)2N(R52)2, -S(=O)2NR53R54, -NR52S(=O)2R52, -NR52S(=O)2N(R52)2, -NR52S(=O)2NR53R54, -C(O)R52, -C(O)OR52, -OC(O)R52, -OC(O)OR52, -OC(O)N(R52)2, -OC(O)NR53R54, -NR52C(O)R52, -NR52C(O)OR52, -NR52C(O)N(R52)2, -NR52C(O)NR53R54, -C(O)N(R52)2, -C(O)NR53R54, -P(O)(OR52)2, - P(O)(R52)2, -P(O)(OR52)(R52), -P(O)(NR52)(R52), -NR52P(O)(R52), -P(O)(NR52)(OR52), -P(O)(NR52)2, =O, =S, =N(R52), C3-12 carbocycle, and 3- to 12- membered heterocycle; wherein each C3-12carbocycle and 3- to 12-membered heterocycle in R56is optionally substituted with one or more substituents independently selected from halogen, -NO2, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=O)R52, -S(=O)2R52, -S(=O)2N(R52)2, -S(=O)2NR53R54, -NR52S(=O)2R52, -NR52S(=O)2N(R52)2, -NR52S(=O)2NR53R54, -C(O)R52, -C(O)OR52, -OC(O)R52, -OC(O)OR52, -OC(O)N(R52)2, -OC(O)NR53R54, -NR52C(O)R52, -NR52C(O)OR52, -NR52C(O)N(R52)2, -NR52C(O)NR53R54, -C(O)N(R52)2, -C(O)NR53R54, -P(O)(OR52)2, - P(O)(R52)2, -P(O)(OR52)(R52), -P(O)(NR52)(R52), -NR52P(O)(R52), -P(O)(NR52)(OR52), -P(O)(NR52)2, =O, =S, =N(R52), C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl; and further wherein R56optionally forms a bond to ring C; and R59is independently selected at each occurrence from C1-20 alkyl, C2-20 alkenyl, C2-20 alkynyl, 1- to 6-membered heteroalkyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each ofWSGR Reference No.47535-754.601 which is optionally substituted by halogen, -CN, -NO2, -NH2, -NHCH3, -NHCH2CH3, =O, - OH, -OCH3, -OCH2CH3, C3-12carbocycle, or 3- to 6-membered heterocycle.

[0046] In some embodiments, for a compound of Formula (I-A) or (I-B), RCis selected from - C(O)R52, -S(=O)R52, -S(=O)2R52, -S(=O)2N(R52)2, -S(=O)2NR53R54, -NR52S(=O)2R52, =O, C1-3 alkyl, and C1-3 haloalkyl; or two RCgroups attached to different atoms can together form a C1-3 bridge.

[0047] In some embodiments of Formula (I-B):each of Z1, Z2, Z3, and Z4is independently selected from -C(RA1)(RA2)-, -C(RA1)(RA2)- C(RA1)(RA2)-, -C(O)-, and -C(RA1)(RA2)-C(O)-, wherein no more than one of Z1, Z2, Z3, and Z4is -C(O)- or -C(RA1)(RA2)-C(O)-; RA1is, at each occurrence, independently selected from hydrogen and R50; RA2is, at each occurrence, independently selected from hydrogen and R50; and each of Z5and Z6is independently selected from -C(H)- and -N-;

[0048] In some embodiments of Formula (I-A) or Formula (I-B), A is. In some embodiments, A is. In some embodiments, A is selected from:.WSGR Reference No.47535-754.601

[0049] In some embodiments, the menin inhibitor is a compound of Formula (II-A):or a pharmaceutically acceptable form thereof, wherein: C is selected from C3-12carbocycle and 3- to 12-membered heterocycle; L2is selected from bond, -C(O)-, -C(O)O-, -C(O)N(R51)-, -C(O)N(R51)C(O)-, -C(O)N(R51)C(O)N(R51)-, -C(NR51)-, -S(O)2-, -S(O)O-, -S(O)-, -S(O)2O-, S(O)2N(R51)-, and -S(O)N(R51)-; and alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, and heteroalkynylene, wherein each of the alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, and heteroalkynylene is optionally substituted with one or more R50; L3is selected from alkylene, alkenylene, and alkynylene, each of which is substituted with one or more R56and optionally further substituted with one or more R50; R1and R3are each independently selected from hydrogen and R50; R2is R50; RA, RB, and RCare each independently selected at each occurrence from R50; or two RAgroups, two RBgroups, or two RCgroups attached to the same atom or different atoms can together optionally form a bridge or ring; m, n, and p are each independently an integer from 0 to 6; R50is independently selected at each occurrence from: halogen, -NO2, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=O)R52, -S(=O)2R52, -S(=O)2N(R52)2, -S(=O)2NR53R54, -NR52S(=O)2R52, -NR52S(=O)2N(R52)2, -NR52S(=O)2NR53R54, -C(O)R52, -C(O)OR52, -OC(O)R52, -OC(O)OR52, -OC(O)N(R52)2, -OC(O)NR53R54, -NR52C(O)R52, -NR52C(O)OR52, -NR52C(O)N(R52)2, -NR52C(O)NR53R54, -C(O)N(R52)2, -C(O)NR53R54, -P(O)(OR52)2, and -P(O)(R52)2; or two R50groups attached to the same atom taken together form =O, =S, or =N(R52); C1-10 alkyl, C2-10 alkenyl, and C2-10 alkynyl, each of which is optionally substituted at each occurrence with one or more substituents independently selected from halogen, -NO2, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=O)R52, -S(=O)2R52, -S(=O)2N(R52)2, -S(=O)2NR53R54, -NR52S(=O)2R52, -NR52S(=O)2N(R52)2, -NR52S(=O)2NR53R54, -C(O)R52, -C(O)OR52, -OC(O)R52, -OC(O)OR52, -OC(O)N(R52)2, -OC(O)NR53R54, -NR52C(O)R52, -NR52C(O)OR52,WSGR Reference No.47535-754.601 -NR52C(O)N(R52)2, -NR52C(O)NR53R54, -C(O)N(R52)2, -C(O)NR53R54, -P(O)(OR52)2, - P(O)(R52)2, =O, =S, =N(R52), C3-12carbocycle, and 3- to 12-membered heterocycle; and C3-12carbocycle and 3- to 12-membered heterocycle, wherein each C3-12 carbocycle and 3- to 12-membered heterocycle in R50is optionally substituted with one or more substituents independently selected from halogen, -NO2, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=O)R52, -S(=O)2R52, -S(=O)2N(R52)2, -S(=O)2NR53R54, -NR52S(=O)2R52, -NR52S(=O)2N(R52)2, -NR52S(=O)2NR53R54, -C(O)R52, -C(O)OR52, -OC(O)R52, -OC(O)OR52, -OC(O)N(R52)2, -OC(O)NR53R54, -NR52C(O)R52, -NR52C(O)OR52, -NR52C(O)N(R52)2, -NR52C(O)NR53R54, -C(O)N(R52)2, -C(O)NR53R54, -P(O)(OR52)2, - P(O)(R52)2, =O, =S, =N(R52), C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl; R51is independently selected at each occurrence from: hydrogen, -C(O)R52, -C(O)OR52, -C(O)N(R52)2, and -C(O)NR53R54; and C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is optionally substituted at each occurrence with one or more substituents independently selected from halogen, -NO2, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=O)R52, -S(=O)2R52, -S(=O)2N(R52)2, -S(=O)2NR53R54, -NR52S(=O)2R52, -NR52S(=O)2N(R52)2, -NR52S(=O)2NR53R54, -C(O)R52, -C(O)OR52, -OC(O)R52, -OC(O)OR52, -OC(O)N(R52)2, -OC(O)NR53R54, -NR52C(O)R52, -NR52C(O)OR52, -NR52C(O)N(R52)2, -NR52C(O)NR53R54, -C(O)N(R52)2, -C(O)NR53R54, -P(O)(OR52)2, - P(O)(R52)2, =O, =S, =N(R52), C3-12 carbocycle, and 3- to 12-membered heterocycle; and C3-12carbocycle and 3- to 12-membered heterocycle, wherein each C3-12carbocycle and 3- to 12-membered heterocycle in R51is optionally substituted with one or more substituents independently selected from halogen, -NO2, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=O)R52, -S(=O)2R52, -S(=O)2N(R52)2, -S(=O)2NR53R54, -NR52S(=O)2R52, -NR52S(=O)2N(R52)2, -NR52S(=O)2NR53R54, -C(O)R52, -C(O)OR52, -OC(O)R52, -OC(O)OR52, -OC(O)N(R52)2, -OC(O)NR53R54, -NR52C(O)R52, -NR52C(O)OR52, -NR52C(O)N(R52)2, -NR52C(O)NR53R54, -C(O)N(R52)2, -C(O)NR53R54, -P(O)(OR52)2, - P(O)(R52)2, =O, =S, =N(R52), C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, and C2-6alkynyl; R52is independently selected at each occurrence from hydrogen; and C1-20 alkyl, C2-20 alkenyl, C2-20 alkynyl, C1-6 heteroalkyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted by halogen, -CN, -NO2, -NH2, -NHCH3, -NHCH2CH3, =O, -OH, -OCH3, -OCH2CH3, C3-12 carbocycle, or 3- to 6-membered heterocycle;WSGR Reference No.47535-754.601 R53and R54are taken together with the nitrogen atom to which they are attached to form a heterocycle; R56is independently selected at each occurrence from: -NO2, -OR59, -SR52, -NR53R54, -S(=O)R52, -S(=O)2R52, -S(=O)2N(R52)2, -S(=O)2NR53R54, -NR52S(=O)2R52, -NR52S(=O)2N(R52)2, -NR52S(=O)2NR53R54, -C(O)R52, -C(O)OR52, -OC(O)R52, -OC(O)OR52, -OC(O)N(R52)2, -OC(O)NR53R54, -NR52C(O)R52, -NR52C(O)OR52, -NR52C(O)N(R52)2, -NR52C(O)NR53R54, -C(O)N(R52)2, -C(O)NR53R54, -P(O)(OR52)2, -P(O)(R52)2, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle; or two R56groups attached to the same atom taken together form =O, =S, or =N(R52); wherein each C1-10 alkyl, C2-10 alkenyl, and C2-10 alkynyl in R56is optionally substituted at each occurrence with one or more substituents independently selected from halogen, - NO2, -CN, -OR59, -SR52, -N(R52)2, -NR53R54, -S(=O)R52, -S(=O)2R52, -S(=O)2N(R52)2, -S(=O)2NR53R54, -NR52S(=O)2R52, -NR52S(=O)2N(R52)2, -NR52S(=O)2NR53R54, -C(O)R52, -C(O)OR52, -OC(O)R52, -OC(O)OR52, -OC(O)N(R52)2, -OC(O)NR53R54, -NR52C(O)R52, -NR52C(O)OR52, -NR52C(O)N(R52)2, -NR52C(O)NR53R54, -C(O)N(R52)2, -C(O)NR53R54, -P(O)(OR52)2, - P(O)(R52)2, =O, =S, =N(R52), C3-12 carbocycle, and 3- to 12-membered heterocycle; wherein each C3-12carbocycle and 3- to 12-membered heterocycle in R56is optionally substituted with one or more substituents independently selected from halogen, -NO2, -CN, -OR52, -SR52, -N(R52)2, -NR53R54, -S(=O)R52, -S(=O)2R52, -S(=O)2N(R52)2, -S(=O)2NR53R54, -NR52S(=O)2R52, -NR52S(=O)2N(R52)2, -NR52S(=O)2NR53R54, -C(O)R52, -C(O)OR52, -OC(O)R52, -OC(O)OR52, -OC(O)N(R52)2, -OC(O)NR53R54, -NR52C(O)R52, -NR52C(O)OR52, -NR52C(O)N(R52)2, -NR52C(O)NR53R54, -C(O)N(R52)2, -C(O)NR53R54, -P(O)(OR52)2, - P(O)(R52)2, =O, =S, =N(R52), C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, and C2-6alkynyl; and further wherein R56optionally forms a bond to ring C; and R59is independently selected at each occurrence from C1-20alkyl, C2-20alkenyl, C2-20alkynyl, C1-6heteroalkyl, C3-12carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted by halogen, -CN, -NO2, -NH2, -NHCH3, -NHCH2CH3, =O, -OH, -OCH3, -OCH2CH3, C3-12 carbocycle, or 3- to 6-membered heterocycle.

[0050] In some embodiments, the menin inhibitor is a compound of Formula (III-A):WSGR Reference No.47535-754.601or a pharmaceutically acceptable form thereof, wherein R2, each RB, each RC, L3, C, and p are each defined as described for Formula (II-A).

[0051] In some embodiments, the menin inhibitor is a compound of Formula (IV-A) or Formula (IV-B):or a pharmaceutically acceptable form thereof, wherein R2, R56, and RCare each defined as described for Formula (II-A).

[0052] In some embodiments, the menin inhibitor is ziftomenib:or a pharmaceutically acceptable form thereof, such as a pharmaceutically acceptable salt or solvate thereof.

[0053] In some embodiments, the menin inhibitor is a compound of Formula (I-A), (I-B), (II- A), (III-A), (IV-A), or (IV-B), or a pharmaceutically acceptable form thereof. In some embodiments, wherein the menin inhibitor is ziftomenib or a pharmaceutically acceptable form thereof.WSGR Reference No.47535-754.601

[0054] The compound of Formula (I-A), Formula (I-B), Formula (II-A), Formula (III-A), Formula (IV-A), or Formula (IV-B) (e.g., ziftomenib) may be synthesized by methods described in U.S. Pat. No.10,781,218 or other U.S. patents described herein.

[0055] In some embodiments, the menin inhibitor is a menin inhibitor described in U.S. Patent No.10,683,302, which disclosure is incorporated by reference herein. In some embodiments, the menin inhibitor is a compound of Formula (A-I):or a pharmaceutically acceptable form thereof, wherein: A, B, D, and E are each independently selected from(RA2)—, —C(RA1)(RA2)— C(RA1)(RA2)—, —C(RA1)(RA2)—O—, —C(RA1)(RA2)—NRA3—, —C(═O)—, C(RA1)(RA2)—C(═O)—, and —N═C(NH2)— wherein no more than one of A, B, D, and E is —C(RA1)(RA2)—O—, —C(RA1)(RA2)—NRA3—, —C(RA1)(RA2)—C(═O)—, —C(═O)—, or —N═C(NH2)—; U is N or CRU, wherein RUis H, halo, CN, OH, C1-4alkyl, C1-4alkoxy, amino, C1-4alkyl amino, or C2-8 dialkylamino; W is N or wherein RWis H, halo, CN, OH, C1-4 alkyl, C1-4 alkoxy, amino, C1-4 alkyl amino, or C2-8dialkylamino; X is N or CRX, wherein RXis H, halo, CN, OH, C1-4 alkyl, C1-4 alkoxy, amino, C1-4 alkyl amino, or C2-8 dialkylamino, wherein when X is N, the atom of L that is directly bonded with X is other than N, O, or S; L is selected from —C1-6alkylene- and —(C1-4alkylene)a-Q-(C1-4alkylene)b-, wherein the C1-6 alkylene group and any C1-4 alkylene group of the —(C1-4 alkylene)a-Q-(C1-4 alkylene)b- group is optionally substituted with 1, 2, or 3 substituents independently selected from halo, CN, OH, C1-3alkyl, C1-3alkoxy, C1-3haloalkyl, C1-3haloalkoxy, amino, C1-3alkylamino, and di(C1-3 alkyl)amino;—C(═NRq2)—, or —C(═NRq2)—NRq1—, wherein each Rq1is independently selected from H or C1-6 alkyl, and wherein each Rq2is independently selected from H, C1-6 alkyl, and CN;WSGR Reference No.47535-754.601 Cy is a linking C6-14 aryl, C3-18 cycloalkyl, 5-16 membered heteroaryl, or 4-18 membered heterocycle group, each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from RCy, wherein the heteroaryl or heterocycle has 1-3 rings and 1-4 heteroatoms independently selected from nitrogen, sulfur, and oxygen; each RCyis independently selected from halo, C1-6 alkyl, C1-4 haloalkyl, C1-4 cyanoalkyl, C2- 6 alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycle, CN, NO2, ORa1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1,NRc1S(O)2NRc1Rd1, S(O)Rb1, S(O)NRc1Rd1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycle are each optionally substituted by 1, 2, 3, or 4 substituents independently selected from CN, NO2, ORa1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, OC(O)Rb1, OC(O)NRc1Rd1, C(═NRe1)NRc1Rd1, NRc1C(═NRe1)NRc1Rd1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1C(O)NRc1Rd1, NRc1S(O)Rb1, NRc1S(O)2Rb1, NRc1S(O)2NRc1Rd1, S(O)Rb1, S(O)NRc1Rd1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein the heteroaryl or heterocycle has 1-3 rings and 1-4 heteroatoms independently selected from nitrogen, sulfur, and oxygen; R1is H, Cy1, halo, C1-6alkyl, C1-4haloalkyl, C1-4cyanoalkyl, C2-6alkenyl, C2-6alkynyl, -CN, -NO2, -ORa2, -SRa2, -C(O)Rb2, -C(O)NRc2Rd2, -C(O)ORa2, -OC(O)Rb2, -OC(O)NRc2Rd2, -C(═NRe2)NRc2Rd2, -NRc2C(═NRe2)NRc2Rd2, -NRc2Rd2, -NRc2C(O)Rb2, -NRc2C(O)ORa2, -NRc2C(O)NRc2Rd2, -NRc2S(O)Rb2, -NRc2S(O)2Rb2, -NRc2S(O)2NRc2Rd2, -S(O)Rb2, -S(O)NRc2Rd2, -S(O)2Rb2and -S(O)2NRc2Rd2, wherein said C1-6alkyl, C2-6alkenyl, and C2-6 alkynyl are each optionally substituted by 1, 2, 3, or 4 substituents independently selected from halo, -CN, -NO2, -ORa2, -SRa2, -C(O)Rb2, -C(O)NRc2Rd2, -C(O)ORa2, -OC(O)Rb2, -OC(O)NRc2Rd2, -C(═NRe2)NRc2Rd2, -NRc2C(═NRe2)NRc2Rd2, -NRc2Rd2, -NRc2C(O)Rb2, -NRc2C(O)ORa2, -NRc2C(O)NRc2Rd2, -NRc2S(O)Rb2, -NRc2S(O)2Rb2, -NRc2S(O)2NRc2Rd2, -S(O)Rb2, -S(O)NRc2Rd2, -S(O)2Rb2, and -S(O)2NRc2Rd2; Y is O, S, CRY1RY2or NRY3, wherein RY1, RY2, and RY3are each independently selected from H and C1-4alkyl; Z is halo, C1-6 alkyl, C1-4 haloalkyl, C1-4 cyanoalkyl, C2-6 alkenyl, C2-6 alkynyl, -CN, -NO2, ORa3, SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, OC(O)Rb3, OC(O)NRc3Rd3, C(═NRe3)NRc3Rd3, NRc3C(═NRe3)NRc3Rd3, NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)ORa3, NRc3C(O)NRc3Rd3, NRc3S(O)Rb3, NRc3S(O)2Rb3, NRc3S(O)2NRc3Rd3, S(O)Rb3, S(O)NRc3Rd3, S(O)2Rb3, S(O)2NRc3Rd3, and P(O)Rc3Rd3wherein said C1-6 alkyl, C2-6 alkenyl,WSGR Reference No.47535-754.601 and C2-6 alkynyl are each optionally substituted by 1, 2, 3, or 4 substituents independently selected from Cy2, halo, CN, NO2, CN, NO2, ORa3, SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, OC(O)Rb3, OC(O)NRc3Rd3, C(═NRe3)NRc3Rd3, NRc3C(═NRe3)NRc3Rd3, NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)ORa3, NRc3C(O)NRc3Rd3, NRc3S(O)Rb3, NRc3S(O)2Rb3, NRc3S(O)2NRc3Rd3, S(O)Rb3, S(O)NRc3Rd3, S(O)2Rb3, and S(O)2NRc3Rd3; each R2and R3is independently selected from H, halo, C1-6alkyl, C1-4haloalkyl, C1-4cyanoalkyl, C2-6 alkenyl, C2-6 alkynyl, CN, NO2, ORa4, SRa4, C(O)Rb4, C(O)NRc4Rd4, C(O)ORa4,said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted by 1, 2, 3, or 4 substituents independently selected from halo, CN, NO2, ORa4, SRa4, C(O)Rb4, C(O)NRc4Rd4, C(O)ORa4, OC(O)Rb4, OC(O)NRc4Rd4, C(═NRe4)NRc4Rd4,each RA1is independently selected from H, halo, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1- 4 haloalkoxy, amino, C1-4 alkylamino, C2-8 dialkylamino, CN, NO2, and OH; each RA2is independently selected from H, halo, C1-4alkyl, C1-4alkoxy, C1-4haloalkyl, C1-4haloalkoxy, amino, C1-4alkylamino, C2-8dialkylamino, CN, NO2, and OH; each RA3is independently selected from H, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C(O)Rz, and C(O)ORz, wherein said C1-4alkyl is optionally substituted by phenyl, C1-4alkoxy, C1-4haloalkoxy, CN, NO2, or OH; Rzis H, C1-4 alkyl, or phenyl; each Cy1is independently selected from C6-14 aryl, C3-18 cycloalkyl, 5-16 membered heteroaryl, and 4-18 membered heterocycle, each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from RCy1, wherein the heteroaryl or heterocycle has 1-3 rings and 1-4 heteroatoms independently selected from nitrogen, sulfur, and oxygen; each Cy2is independently selected from C6-14aryl, C3-18cycloalkyl, 5-16 membered heteroaryl, and 4-18 membered heterocycle, each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from RCy2, wherein the heteroaryl or has 1-3 rings and 1- 4 heteroatoms independently selected from nitrogen, sulfur, and oxygen; each RCy1and RCy2is independently selected from halo, C1-6alkyl, C1-4haloalkyl, C1-4 cyanoalkyl, C2-6 alkenyl, C2-6 alkynyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, and 4-7 membered heterocycle, CN, NO2, ORa5, SRa5, C(O)Rb5, C(O)NRc5Rd5, C(O)ORa5,WSGR Reference No.47535-754.601 OC(O)Rb5, OC(O)NRc5Rd5, C(═NRe5)NRc5Rd5, NRc5C(═NRe5)NRc5Rd5, NRc5Rd5, NRc5C(O)Rb5, NRc5C(O)ORa5, NRc5C(O)NRc5Rd5, NRc5S(O)Rb5, NRc5S(O)2Rb5, NRc5S(O)2NRc5Rd5, S(O)Rb5, S(O)NRc5Rd5, S(O)2Rb5, and S(O)2NRC5Rd5, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, and 4-7 membered heterocycle are each optionally substituted by 1, 2, 3, or 4 substituents independently selected from CN, NO2, ORa5, SRa5, C(O)Rb5, C(O)NRc5Rd5, C(O)ORa5, OC(O)Rb5, OC(O)NRc5Rd5, C(═NRe5)NRc5Rd5, NRc5C(═NRe5)NRc5Rd5, NRc5Rd5, NRc5C(O)Rb5, NRc5C(O)ORa5, NRc5C(O)NRc5Rd5NRc5S(O)Rb5, NRc5S(O)2Rb5, NRc5S(O)2NRc5Rd5, S(O)Rb5, S(O)NRc5Rd5, S(O)2Rb5, and S(O)2NRc5Rd5, wherein the heteroaryl or heterocycle has 1-3 rings and 1-4 heteroatoms independently selected from nitrogen, sulfur, and oxygen; each Ra1, Rb1, Rc1, Rd1, Ra2, Rb2, Rc2, Rd2, Ra3, Rb3, Rc3, Rd3, Ra4, Rb4, Rc4, Rd4, Ra5, Rb5, Rc5, and Rd5is independently selected from H, C1-6alkyl, C1-4haloalkyl, C2-6alkenyl, C2-6alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycle, C6-10 aryl- C1-6 alkyl, C3-10 cycloalkyl-C1-6 alkyl, (5-10 membered heteroaryl)-C1-6 alkyl, and (4-10 membered heterocycle)-C1-6alkyl, wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycle, C6-10 aryl- C1-6 alkyl, C3-10 cycloalky-C1-6 alkyl, (5-10 membered heteroaryl)-C1-6 alkyl, and (4-10 membered heterocycle)-C1-6alkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Rg, wherein the heteroaryl or heterocycle has 1-3 rings and 1-4 heteroatoms independently selected from nitrogen, sulfur, and oxygen; each Re1, Re2, Re3, Re4, and Re5is independently selected from H, C1-4alkyl, and CN; each Rgis independently selected from the group consisting of OH, NO2, CN, halo, C1-6alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, cyano-C1-3 alkyl, HO—C1-3 alkyl, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, thiol, C1-6 alkylthio, C1- 6 alkylsulfinyl, C1-6alkylsulfonyl, carboxy, aminocarbonyl, C1-6alkylcarbonyl, and C1-6alkoxycarbonyl; n is 0 or 1; m is 0 or 1; p is 0, 1, 2, or 3; q is 0, 1, or 2; a is 0 or 1; and b is 0 or 1, wherein any cycloalkyl or heterocycle group is optionally further substituted by 1 or 2 oxo groups.WSGR Reference No.47535-754.601

[0056] In one embodiment, the menin inhibitor is SNDX-5613 (revumenib):(revumenib) or a pharmaceutically acceptable form thereof.

[0057] In another embodiment, the menin inhibitor is VTP-50469:; or a pharmaceutically acceptable form thereof.

[0058] In some embodiments, the menin inhibitor is a menin inhibitor described in U.S. Pat. Publ. No.20210269454, which disclosure is incorporated by reference herein. In some embodiments, the menin inhibitor is a compound of Formula (A-II):wherein the dotted circle indicates that the ring is aromatic, R1and R2are each independently a hydrogen atom or a C1-6alkyl group, one of R3and R4is a hydrogen atom, a hydroxy group, a halogen atom, a C1-6 alkoxy group, a di(C1-6 alkyl)carbamoyl group, or an oxazolyl group, and the other of R3and R4is a hydrogen atom, a hydroxy group, a halogen atom, or a C1-6 alkoxy group, R5is a hydrogen atom, a C1-6alkyl group, or a hydroxy C1-6alkyl group, R6is a hydrogen atom, a C1-6 alkyl group, a halogen atom, a C1-6 alkoxy group, an amino group, or a C1-6 alkylamino group,WSGR Reference No.47535-754.601 R7and R8are taken together with the carbon atom to which R7is bonded and the carbon atom to which R8is bonded to form any of the following formulas (2A) to (2C):wherein the dotted circle indicates that the ring is aromatic, the carbon atom marked with a is the carbon atom to which R8is bonded, the carbon atom marked with b is the carbon atom to which R7is bonded, X is CH or a nitrogen atom, and R9is a halogen, C1-6 alkyl group, a C3-8 cycloalkyl group, a C3-8cycloalkyl C1-6alkyl group, a C1-6alkoxy C1-6alkyl group, or an oxetanyl group, or R7is a hydrogen atom, and R8is the following formula (3):wherein * indicates a bonding site, R10is a di(C1-6alkyl) carbamoyl group, a (C1-6alkyl)pyrimidinyl group, a (C1-6alkyl)phenyl group, or a (C1-6 alkyl)pyrazolyl group, R11is a hydrogen atom or a halogen atom, and R12is a halogen atom, m is 1 or 0, n is 1 or 2, Ring Q1is a 6-membered aromatic ring optionally containing one nitrogen atom in the ring (the aromatic ring optionally has one or two substituents independently selected from the following Group A), a 5-membered aromatic heterocycle containing, in the ring, one or two heteroatoms independently selected from the group consisting of a nitrogen atom and a sulfur atom (the aromatic heterocycle optionally has one substituent independently selected from the following Group A), a C3-8 cycloalkane ring optionally having one substituent independently selected from the following Group A, a C4-8 cycloalkene ring optionally having one substituent independently selected from the following Group A, a 4- to 8-membered saturated heterocycle containing oneWSGR Reference No.47535-754.601 nitrogen atom in the ring (the saturated heterocycle optionally has one substituent independently selected from the following Group A), or a 9-membered bicyclic aromatic heterocycle containing one nitrogen atom in the ring (the bicyclic aromatic heterocycle optionally has one or two substituents independently selected from the following Group B), and W is the following formula (4A) or (4B):wherein * indicates a bonding site, Ring Q2is a 6-membered aromatic ring optionally containing one nitrogen atom in the ring (the aromatic ring optionally has one to three substituents independently selected from the following Group C), a 6-membered aromatic heterocycle containing two nitrogen atoms in the ring (the aromatic heterocycle optionally has one to three substituents independently selected from the following Group C), a 5-membered aromatic heterocycle containing, in the ring, one to three heteroatoms independently selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom (the aromatic heterocycle optionally has one substituent independently selected from the following Group C), a 9- or 10-membered bicyclic aromatic or partially unsaturated heterocycle containing, in the ring, one to three heteroatoms independently selected from the group consisting of a nitrogen atom and an oxygen atom (the bicyclic aromatic or partially unsaturated heterocycle optionally has one or two substituents independently selected from the following Group D), a 5- to 8-membered saturated heterocycle containing, in the ring, one or two heteroatoms independently selected from the group consisting of an oxygen atom and a nitrogen atom (the saturated heterocycle optionally has one substituent independently selected from the following Group E), or a C3-8 cycloalkane ring optionally having one substituent independently selected from the following Group E, Ring Q3is a 4- to 8-membered saturated heterocycle containing one nitrogen atom or one oxygen atom in the ring (the saturated heterocycle optionally has one C1-6alkylsulfonyl group), or a 6-membered aromatic ring optionally containing one nitrogen atom in the ring (the aromatic ring optionally has one substituent independently selected from the following Group F), Y is a single bond or an oxygen atom, and Z is a single bond, an oxygen atom, —NH—, —SO2—, a C1-6 alkylene group, *—R13—WSGR Reference No.47535-754.601 wherein * is bonded to Ring Q2, ** is bonded to Ring Q1, and R13, R14and R15are each independently a C1-6alkylene group, Group A: a halogen atom, a hydroxy group, a C1-6alkyl group, a C1-6alkoxy group, a hydroxy C1-6 alkoxy group, a vinylsulfonylamino(C1-6 alkyl)carbamoyl group, and a prop-2- enoylamino(C1-6 alkyl)carbamoyl group, Group B: a cyano group, a C1-6alkyl group, a halogen atom, and a C1-6alkoxy group, Group C: a halogen atom, a C1-6 alkyl group, a C1-6 alkoxy group, a C1-6 alkyl(C1- 6 alkylsulfonyl)amino group, a cyano group, a C1-6 alkylsulfonyl group, a C1-6 alkylamino group, a di(C1-6alkyl)amino group, a halogeno C1-6alkyl group, a C1-6alkoxy C1-6alkoxy group, a halogeno C1-6alkoxy group, a C1-6alkylsulfonyl C1-6alkyl group, a di(C1-6alkyl)sulfamoyl group, a C1-6 alkylenedioxy group, a (C1-6 alkyl)carbamoyl group, a hydroxy C1-6 alkyl group, a 2-C3-6alkenoylamino group, a C1-6alkyl (2-C3-6alkenoyl)amino group, a hydroxy group, an oxo group, a -OC(2H)3group,group, Group D: a halogen atom, a C1-6 alkyl group, and a C1-6 alkylsulfonyl group, Group E: an oxo group, a hydroxy group, and a C1-6 alkoxy group, and Group F: a halogen atom, and a C1-6alkoxy group.

[0059] In some embodiments, the menin inhibitor is Compound A:Compound A, or a pharmaceutically acceptable form thereof.

[0060] In some embodiments, the menin inhibitor is a menin inhibitor described in PCT Publ. No. WO2021 / 121327, which disclosure is incorporated by reference herein. In some embodiments, the menin inhibitor is a compound of Formula (A-III):or a pharmaceutically acceptable form thereof, whereinWSGR Reference No.47535-754.601 R1arepresents -Het represents a 5- or 6-membered monocyclic aromatic ring containing one, two or three nitrogen atoms and optionally a carbonyl moiety; wherein said 5- or 6-membered monocyclic aromatic ring is optionally substituted with one or two substituents selected from the group consisting of C3-6cycloalkyl and C1-4alkyl; Rxaand Rxbare each independently selected from the group consisting of hydrogen, C1-4alkyl and C3-6cycloalkyl; R1brepresents F or Cl; Y1represents -CR5aR5b-, -O- or -NR5c-; R2is selected from the group consisting of hydrogen, halo, C1-4alkyl, -O-C1-4alkyl, and - NR7aR7b; U represents N or CH; n1, n2, n3 and n4 are each independently selected from 1 and 2; X1represents CH, and X2represents N; R4represents isopropyl; R5a, R5b, R5c, R7a, and R7b, are each independently selected from the group consisting of hydrogen, C1-4alkyl and C3-6cycloalkyl; R3represents -C1-6alkyl-NR8aR8b, C1-6alkyl-C(=O)-NR9aR9b, -C1-6alkyl-OH, or -C1-6alkyl-NR11- C(=O)-O-C1-4alkyl-O-C(=O)-C1-4alkyl; wherein each of the C1-4alkyl or C1-6alkyl moieties in the R3definitions independently of each other may be substituted with one, two or three substituents each independently selected from the group consisting of cyano, halo, -OH, and -O-C1-4alkyl; R8aand R8bare each independently selected from the group consisting of hydrogen; C1-6alkyl; - C(=O)-C1-4alkyl; -C(=O)-O-C1-4alkyl; -C(=O)-NR12R12b); and C1-6a1ky1 substituted with one, two or three substituents each independently selected from the group consisting of -OH, cyano, halo, -S(=O)2-C1-4alkyl, -O-C1-4alkyl, -C(=O)-NR10aR10b, and -NR10c-C(=O)-C1-4alkyl; R9a, R9b, R10a, R10b, R10c, R11, R12a, and R12bare each independently selected from the group consisting of hydrogen and C1-6alkyl.

[0061] In one embodiment, the menin inhibitor is Compound B1:WSGR Reference No.47535-754.601or a pharmaceutically acceptable form thereof.

[0062] In one embodiment, the menin inhibitor is Compound B2:or a pharmaceutically acceptable form thereof.

[0063] In some embodiments, the menin inhibitor is a menin inhibitor described in U.S. Patent No.11,084,825, which disclosure is incorporated by reference herein. In some embodiments, the menin inhibitor is a compound of Formula (A-IV):or a pharmaceutically acceptable form thereof, wherein: A is N; Cy is:WSGR Reference No.47535-754.601wherein Cy is optionally substituted with one or more independently selected R7substituents;W is —C(O)—, Y is a single bond,—O—; (i) R1is H, halo, CN, C1-6alkyl, or C1-6haloalkyl; andR2is H, halo, CN, C1-6alkyl, or C1-6haloalkyl; each R3ais independently H or C1-6alkyl; each R3bis independently H or C1-6 alkyl; each R4ais independently H, halo, CN, C1-6alkyl, C(O)R, C(O)N(R)2, C(O)OR, N(R)2, NRC(O)R, OR, S(O)2R, C3-7cycloalkyl, a 4- to 7-membered heterocycloalkyl ring, phenyl, an 8- to 10-membered bicyclic aryl ring, or a 5- or 6-membered heteroaryl ring, wherein the 4- to 7- membered heterocycloalkyl ring has 1 or 2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, and the 5- or 6-membered heteroaryl ring has 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur;WSGR Reference No.47535-754.601 each R4bis independently H, halo, CN, C1-6 alkyl, C(O)R, C(O)N(R)2, C(O)OR, N(R)2, NRC(O)R, OR, S(O)2R, C3-7cycloalkyl, a 4- to 7-membered heterocycloalkyl ring, phenyl, an 8- to 10-membered bicyclic aryl ring, or a 5- or 6-membered heteroaryl ring, wherein the 4- to 7- membered heterocycloalkyl ring has 1 or 2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, and the 5- or 6-membered heteroaryl ring has 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; each R7is independently a 4- to 7-membered heterocycloalkyl ring, phenyl, an 8- to 10- membered bicyclic aryl ring, or a 5- or 6-membered heteroaryl ring, wherein each 4- to 7- membered heterocycloalkyl ring independently has 1 or 2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, and each 5- or 6-membered heteroaryl ring independently has 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, and further wherein each 4- to 7-membered heterocycloalkyl ring, phenyl, 8- to 10-membered bicyclic aryl ring, and 5- or 6-membered heteroaryl ring is optionally and independently substituted with one or more substituents independently selected from the group consisting of halo, CN, C1-6alkyl, C1-6haloalkyl, NH2, NH(C1-6 alkyl), N(C1-6 alkyl)2, OH, and O(C1-6 alkyl); each R is independently H, C1-6 aliphatic, a saturated or partially unsaturated 4- to 7-membered heterocyclic ring, phenyl, an 8- to 10-membered bicyclic aryl ring, or a 5- or 6-membered heteroaryl ring, wherein the saturated or partially unsaturated 4- to 7-membered heterocyclic ring has 1 or 2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, and the 5- or 6-membered heteroaryl ring has 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; or two geminal R groups, together with the nitrogen atom to which they are attached, form a saturated or partially unsaturated 4- to 7-membered heterocyclic ring or a 5- or 6-membered heteroaryl ring, wherein the 4- to 7-membered heterocyclic ring or the 5- or 6-membered heteroaryl ring has 0, 1, 2, or 3 additional heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; R5ais H, halo, CN, C1-6alkyl, or C1-6haloalkyl;alkyl; R6bis H or C1-6 alkyl; or R6aand R6b, joined together, form a single bond; R6cis H or C1-6alkyl, wherein the C1-6alkyl is optionally substituted with N(CH3)2;WSGR Reference No.47535-754.601 Cy2is a 4- to 7-membered heterocycloalkyl ring, phenyl, or pyridyl, wherein the 4- to 7- membered heterocycloalkyl ring has 1 or 2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; m is 1, 2, or 3; and n is 1, 2, 3, or 4.

[0064] In one embodiment, the menin inhibitor is Compound C:or a pharmaceutically acceptable form thereof.

[0065] In some embodiments, the menin inhibitor is ziftomenib, SNDX-5613 (revumenib), VTP-50469, JNJ-75276617, DS-1594, DS-1594a, DS-1594b, DSP-5336, MI-3454, M-808, A300-105A, BN104, Compound A, Compound B1, Compound B2, or Compound C, or a pharmaceutically acceptable form thereof.

[0066] The compound DSP-5336 has the following structure:.

[0067] In some embodiments, the menin inhibitor is ziftomenib, SNDX-5613 (revumenib), VTP-50469, JNJ-75276617, Compound A, Compound B1, Compound B2, or Compound C, or a pharmaceutically acceptable form thereof.

[0068] In some embodiments, the menin inhibitor is ziftomenib, SNDX-5613 (revumenib), VTP-50469, or Compound A, or a pharmaceutically acceptable form thereof. Ziftomenib and Pharmaceutically Acceptable Forms

[0069] Ziftomenib (KO-539; alternatively named as (S)-4-methyl-5-((4-((2-(methylamino)-6- (2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1-(2-(4- (methylsulfonyl)piperazin-1-yl)propyl)-1H-indole-2-carbonitrile) is potent and selectiveWSGR Reference No.47535-754.601 inhibitor of the menin-KMT2A(MLL) complex that has downstream effects on HOXA9 / MEIS1 expression. (Burrows et al., Proceedings of the AACR EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl): Abstract nr LB-A27.) Ziftomenib is in clinical development for the treatment of acute leukemias, including NMP1-mutated (NPM1-m) and KMT2A-rearranged (KMT2A-r) AML. (See https: / / kuraoncology.com / clinical-trials / clinical- trials-komet-001 / .)

[0070] In some embodiments, the menin inhibitor described herein is ziftomenib or a pharmaceutically acceptable form thereof. In some embodiments, the methods described herein employ a pharmaceutically acceptable form of ziftomenib. In some embodiments, the methods described herein employ ziftomenib or a pharmaceutically acceptable salt thereof. In some embodiments, the methods described herein employ ziftomenib or a solvate thereof. In certain embodiments, ziftomenib comprises the free base form or a solvate thereof. Also included, in some embodiments, are stereoisomers and / or metabolites of ziftomenib. Doses and Dosing Regimens of Menin Inhibitors

[0071] In certain embodiments, dosages, treatment regimens, and effective amounts vary depending on the severity of the disease, the age and relative health of the subject, the potency of the compound(s) used and other factors. In some embodiments, the methods provided herein comprise administering a menin inhibitor to an individual. In some embodiments, the methods provided herein comprise administering an effective amount of a menin inhibitor to an individual.

[0072] In some embodiments, the amount of the menin inhibitor administered in the methods provided herein is from 5 mg / day up to, and including, 2000 mg / day. In some embodiments, the daily dosage of the menin inhibitor is from about 50 mg to about 800 mg. In some embodiments, the daily dosage of the menin inhibitor is from about 50 mg to about 600 mg. In some embodiments, the daily dosage of the menin inhibitor is from about 50 mg to about 400 mg. In some embodiments, the daily dosage of the menin inhibitor is about 50 mg. In some embodiments, the daily dosage of the menin inhibitor is about 100 mg. In some embodiments, the daily dosage of the menin inhibitor is about 200 mg. In some embodiments, the daily dosage of the menin inhibitor is about 400 mg. In some embodiments, the daily dosage of the menin inhibitor is about 600 mg. In some embodiments, the daily dosage of the menin inhibitor is about 800 mg. In some embodiments, the menin inhibitor is ziftomenib and the daily dosage is about 200, 400, 600, or 800 mg. In some embodiments, the menin inhibitor is administered at a dose of about 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 250,WSGR Reference No.47535-754.601 300, 350, 360, 400, 450, 500, 550, 600, or 800 mg / day. In some embodiments, the product labeling for the menin inhibitor does not require it to be administered in combination with a CYP3A4 inhibitor.

[0073] In some embodiments, a daily dose is given once a day, or is divided and given twice a day, three times per day, four times per day to equal the daily dose. In some embodiments, the menin inhibitor is administered at a unit dose of 25 mg, 50 mg, or 200 mg, in a number of unit doses necessary to provide the daily dose. In some embodiments, a unit dose is given once a day, given twice a day, given three times per day, or given four times per day. In some embodiments, one unit dose is given per day, two unit doses are given per day, three unit doses are given per day, or four unit doses are given per day. In some embodiments, two unit doses are given twice per day. In some embodiments, three unit doses are given once per day. In some embodiments, four unit doses are given once per day. In some embodiments, the menin inhibitor is ziftomenib, which is administered at a dose of 200 mg once per day. In some embodiments, the 200 mg once per day dose comprises one 200 mg unit dose. In some embodiments, the menin inhibitor is ziftomenib, which is administered at a dose of 400 mg once per day. In some embodiments, the 400 mg once per day dose comprises two 200 mg unit doses. In some embodiments, the menin inhibitor is ziftomenib, which is administered at a dose of 600 mg once per day. In some embodiments, the 600 mg once per day dose comprises three 200 mg unit doses.

[0074] In some embodiments, the menin inhibitor is SNDX-5613 (revumenib) and the amount administered is 75 mg, 113 mg, 163 mg, 164 mg, or 226 mg once or twice per day, or is from about 163 mg to about 276 mg, or is about 163 mg, or is about 226 mg, or is about 276 mg, in each case every 8 hours or every 12 hours. In some embodiments, revumenib is administered in combination with a CYP3A4 inhibitor. In some embodiments, the menin inhibitor is Compound C and the amount administered is 25, 50, 75, 100, 15, 175, 200, 325, 500, or 650 mg once per day. In some embodiments, the menin inhibitor is Compound B1 or Compound B2 and the daily dose is 5 to 1000 mg / day.

[0075] In some embodiments, the administering of ziftomenib or the pharmaceutically acceptable form thereof comprises administering to the individual for at least 3 days, or for at least 5 days, or for at least 7 days, or for at least 10 days, or for at least 14 days, or for at least 21 days, or for at least 28 days. In some embodiments, ziftomenib or the pharmaceutically acceptable form thereof is administered for at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 3 months, at least 4 months, at least 6 months, or at least a year. In some embodiments, the administering of ziftomenib or the pharmaceutically acceptable form thereof is continuous or is continuous except for drug holiday periods where no menin inhibitor is administered, e.g., for aWSGR Reference No.47535-754.601 period of 1 to 28 days, and administering is resumed following the drug holiday. In some embodiments, the administering of ziftomenib or the pharmaceutically acceptable form thereof is daily for one to 12 cycles, or for one to 12 months, or for one to nine months, followed by a drug holiday of, for example, 7 to 28 days, or 7 to 56 days, or 7 to 84 days, or at least 7 days but not longer than one, two, three, four, five, or six months. A cycle is a period of time where ziftomenib or the pharmaceutically acceptable form thereof is administered at a predetermined length, for example, for 3 days, or for 5 days, or for 7 days, or for 10 days, or for 14 days, or for 21 days, or for 28 days. In some embodiments, the menin inhibitor is administered on an intermittent dosing schedule, such as every other day, or daily but every other week.

[0076] In certain embodiments, ziftomenib or a pharmaceutically acceptable form thereof is administered orally.

[0077] In some embodiments, administering daily is administering once or twice daily. In some embodiments, administering daily is once daily. In some embodiments, the menin inhibitor is administered daily, intermittently, every other day, daily every other week, once per day, twice per day, or three times per day.

[0078] Dose amounts of the menin inhibitors (such as ziftomenib) as presented herein refer to the free base amount (if using the free form) or to the free base equivalent amount (if using a salt and / or solvate). Thus, for example, if a salt form were used, the total amount of a given agent that is administered would exceed the dose of active form, but would be used in a scaled amount to provide the target dose of active agent. Glycemic Conditions, Efficacy, Safety

[0079] In some embodiments, the individual to be treated with the menin inhibitor is in need of improved glycemic control. In some embodiments, the individual has elevated %HbA1c, elevated fasting blood glucose (FBG), impaired postprandial glucose control (e.g., elevated postprandial glucose concentration), elevated HOMA-IR, diminished HOMA-B, reduced fasting plasma insulin concentration, reduced c-peptide concentration, elevated body weight, impaired insulin sensitivity, or any combination thereof. In some embodiments, the individual has type 2 diabetes. In some embodiments, the individual receives insulin therapy (prior to the administering or concomitantly with the menin inhibitor, or both) due to uncontrolled diabetes, optionally due to decline in β-cell function. In some embodiments, the individual receives insulin therapy because of one or more of the following parameters: a) an A1C that is uncontrolled after greater than 3 months of triple combination therapy (metformin plus a DPP-4 inhibitor or a GLP-1 receptor agonist plus an SGLT2 inhibitor or thiazolidinedione, e.g., Trijardy XR (empagliflozin, linagliptin, and metformin hydrochloride) or Qternmet XRWSGR Reference No.47535-754.601 (dapagliflozin, saxagliptin, and metformin); b) an A1C that is >10%, c) a blood glucose that is >300 mg / dL, or d) symptoms of hyperglycemia.

[0080] In some embodiments, the administering reduces the individual’s %HbA1c. In some embodiments, the administering reduces the individual’s FGB. In some embodiments, the administering improves the individual’s postprandial glucose control (e.g., postprandial glucose concentration). In some embodiments, the administering reduces the individual’s HOMA-IR. In some embodiments, the administering increases the individual’s HOMA-B (i.e., improves pancreatic β-cell function). In some embodiments, the administering increases the individual’s fasting plasma insulin concentration. In some embodiments, the administering increases the individual’s c-peptide concentration. In some embodiments, the administering reduces the individual’s body weight. In some embodiments, the administering improves the individual’s insulin sensitivity. In some embodiments, the administering increases proliferation of islet β- cells. In some embodiments, the administering produces any combination of two or more of these effects.

[0081] In some embodiments, provided herein is a method of reducing the %HbA1c in an individual comprising administering to the individual a menin inhibitor. In some embodiments, provided herein is a method of improving glycemic control in an individual comprising administering a menin inhibitor to the individual, wherein the administering reduces the %HbA1c in the individual.

[0082] In some embodiments, the individual’s %HbA1c prior to the administering is in the range of 5.7 to 6.4%. In some embodiments, the individual’s %HbA1c prior to the administering is 6.5% or higher. In some embodiments, the individual’s %HbA1c prior to the administering is 7.0% or higher. In some embodiments, prior to the administering, the individual’s %HbA1c is elevated above normal. In some embodiments, prior to the administering, the individual’s %HbA1c is greater than 5.7%.

[0083] In some embodiments, administering according to the methods described herein reduces %HbA1c in the individual by at least 0.5pp, at least 0.6pp, at least 0.7pp, at least 0.8pp, at least 0.9pp, at least 1pp, at least 1.1pp, at least 1.2pp, at least 1.3pp, at least 1.4pp, at least 1.5pp, at least 1.6pp, at least 1.7pp, at least 1.8pp, at least 1.9pp, or at least 2.0pp, or from 0.5 to 2.0pp, or from 0.8 to 1.8pp, or from 1.0 to 1.8pp, or about 0.5pp, 0.6pp, 0.7pp, 0.8pp, 0.9pp, 1.0pp, 1.1pp, 1.2pp, 1.3pp, 1.4pp, 1.5pp, 1.6pp, 1.7pp, 1.8pp, 1.9pp, or 2.0pp, or to a %HbA1c of less than 7.0%, less than 6.5%, less than 6.4%, less than 6.3%, less than 6.2%, less than 6.1%, less than 6.0%, less than 5.9%, less than 5.8%, or less than 5.7%, or to a %HbA1c of about 5.7 to 6.4%, or to a %HbA1c of 5.7% or less.WSGR Reference No.47535-754.601

[0084] In some embodiments, the administering reduces the %HbA1c within 12 months, 9 months, 6 months, 5 months, 4 months, 3 months, 2 months, 1 month, 56 weeks, 52 weeks, 48 weeks, 40 weeks, 32 weeks, 28 weeks, 24 weeks, 20 weeks, 16 weeks, 12 weeks, 8 weeks, 6 weeks, 5 weeks, 4 weeks, 3 weeks, 2 weeks, or 1 week.

[0085] In some embodiments, the administering reduces the %HbA1c by at least 0.8pp, at least 0.9pp, at least 1pp, at least 1.1pp, at least 1.2pp, at least 1.3pp, at least 1.4pp, at least 1.5pp, at least 1.6pp, from 0.8 to 1.8pp, or from 1.0 to 1.8pp, or to a %HbA1c of about 5.7 to 6.4%, or to a %HbA1c of 5.7% or less, within 12 months, 9 months, 6 months, 5 months, 4 months, 3 months, 2 months, 1 month, 6 weeks, 5 weeks, or 4 weeks.

[0086] In some embodiments, provided herein is a method of reducing body weight in an individual comprising administering to the individual a menin inhibitor. In some embodiments, provided herein is a method of improving glycemic control in an individual comprising administering a menin inhibitor to the individual, wherein the administering reduces the body weight in the individual.

[0087] In some embodiments, the administering reduces the body weight of the individual. In some embodiments, the administering reduces body weight in the individual without significant toxicity or significant reduction in appetite or food intake. In some embodiments, the administering reduces the body weight in the individual within 4 weeks, 6 weeks, 8 weeks, 10 weeks, or 12 weeks, optionally by at least 5%, or at least 10%, or at least 15%, or at least 20%, or by about 5 to 10%, or by about 10 to 20%.

[0088] In some embodiments, provided herein is a method of reducing the FBG in an individual comprising administering to the individual a menin inhibitor. In some embodiments, provided herein is a method of improving glycemic control in an individual comprising administering a menin inhibitor to the individual, wherein the administering reduces the FBG in the individual.

[0089] In some embodiments, prior to the administering, the individual’s FBG is at least 100 mg / dL or 5.6 mmol / L. In some embodiments, the individual’s FBG is from 100 to 125 mg / dL (5.6 to 6.9 mmol / L). In some embodiments, the individual’s FBG is greater than 125 mg / dL (7 mmol / L). In some embodiments, the individual’s FBG is elevated above normal. In some embodiments, the individual’s FBG is greater than 70, greater than 80, greater than 90, or greater than 100 mg / dL.

[0090] In some embodiments, the administering reduces the fasting blood glucose in the individual. In some embodiments, the administering reduces the fasting blood glucose in the individual by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, or atWSGR Reference No.47535-754.601 least 75%. In some embodiments, the administering reduces the fasting blood glucose in the individual to below 10 mmol / L, or below 9 mmol / L, or below 8 mmol / L, or below 7.5 mmol / L, or below 7.0 mmol / L, or below 6.5 mmol / L, or below 6.0 mmol / L, or below 5.6 mmol / L, or below 5.5 mmol / L, or below 5.0 mmol / L, or to about 6.5 to 7.5 mmol / L, or to about 7.0 to 7.5 mmol / L, or to about 5.0 to 8.0 mmol / L, or to about 3.9 mmol / L to 6.9 mmol / L, or to about 3.9 mmol / L to 5.6 mmol / L; or below 150 mg / dL, or below 126 mg / dL, or to a level of 100 to 125 mg / dL, or to a level of 70 to 100 mg / dL; or by at least 10 mg / dL, at least 15 mg / dL, at least 20 mg / dL, at least 25 mg / dL, or at least 30 mg / dL, or at least 35 mg / dL, or at least 40 mg / dL, or at least 45 mg / dL, or at least 50 mg / dL. In some embodiments, the administering reduces the fasting blood glucose in the individual within 60 weeks, 56 weeks, 52 weeks, 48 weeks, 40 weeks, 36 weeks, 30 weeks, 24 weeks, 12 weeks, 10 weeks, 8 weeks, 7 weeks, 6 weeks, 5 weeks, 4 weeks, 3 weeks, 2 weeks, or 1 week. In some embodiments, the administering reduces the fasting blood glucose level for at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, or at least 12 months.

[0091] In some embodiments, provided herein is a method that improves postprandial glucose control (e.g., reduces postprandial glucose concentration) in an individual comprising administering to the individual a menin inhibitor. In some embodiments, provided herein is a method of improving glycemic control in an individual comprising administering a menin inhibitor to the individual, wherein the administering improves postprandial glucose control (e.g., reduces postprandial glucose concentration) in the individual.

[0092] In some embodiments, prior to the administering, the individual’s 2-hour postprandial glucose concentration is at least 140 mg / dL. In some embodiments, the individual’s 2-hour postprandial glucose concentration is from 140 to 180 mg / dL. In some embodiments, the individual’s 2-hour postprandial glucose concentration is at least 181 mg / dL. In some embodiments, the individual’s 2-hour postprandial glucose concentration is from 140 to 199 mg / dL. In some embodiments, the individual’s 2-hour postprandial glucose concentration is at least 200 mg / dL. In some embodiments, the individual’s postprandial glucose concentration (e.g., 2-hour postprandial glucose concentration) is elevated over normal.

[0093] In some embodiments, the administering limits the individual’s 2-hour postprandial glucose concentration during an oral glucose tolerance test to less than 200 mg / dL, or less than 190 mg / dL, or less than 180 mg / dL, or less than 170 mg / dL, or less than 160 mg / dL, or less than 150 mg / dL, or less than 140 mg / dL, or to 130 to 200 mg / dL; or to an amount that is at least 25, at least 50, at least 60, or at least 70 mg / dL less than placebo.

[0094] In some embodiments, provided herein is a method that improves insulin sensitivity in an individual comprising administering to the individual a menin inhibitor. In someWSGR Reference No.47535-754.601 embodiments, provided herein is a method of improving glycemic control in an individual comprising administering a menin inhibitor to the individual, wherein the administering improves insulin sensitivity in the individual.

[0095] In some embodiments, prior to the administering, the individual’s HOMA-IR is at least 1.0, or at least 1.5, or at least 1.9, or at least 2.5, or at least 2.9.

[0096] In some embodiments, the administering reduces the HOMA-IR for the individual to less than 2.9, less than 2.8, less than 2.7, less than 2.6, less than 2.5, less than 2.4, less than 2.3, less than 2.2, less than 2.1, less than 2.0, less than 1.9, less than 1.8, less than 1.7, less than 1.6, less than 1.5, less than 1.4, less than 1.3, less than 1.2, less than 1.1, or less than 1.0. In some embodiments, the administering reduces the HOMA-IR within 4 weeks, 3 weeks, 2 weeks, or 1 week. In some embodiments, the administering reduces the HOMA-IR without significant toxicity or significant reduction in appetite or food intake.

[0097] In some embodiments, provided herein is a method that improves pancreatic β-cell function in an individual comprising administering to the individual a menin inhibitor. In some embodiments, improving pancreatic β-cell function in an individual comprises increasing a HOMA-B value for the individual. In some embodiments, prior to the administering, the individual’s HOMA-B is less than 100. In some In some embodiments, prior to the administering, the individual’s HOMA-B is less than 80, less than 70, less than 60, or less than 50. In some embodiments, the administering increases the HOMA-B for the individual to at least 80, at least 100, or at least 120. In some embodiments, the administering increases a HOMA-B for the individual by at least at least 1.1 times, at least 1.2 times, at least 1.3 times, 1.4 times, at least 1.5 times, at least 2 times, at least 2.5 times, or at least 3 times over the HOMA-B value for the individual prior to administering the menin inhibitor

[0098] In some embodiments, provided herein is a method of increasing the fasting plasma insulin concentration in an individual comprising administering to the individual a menin inhibitor. In some embodiments, provided herein is a method of improving glycemic control in an individual comprising administering a menin inhibitor to the individual, wherein the administering increases the fasting plasma insulin concentration in the individual.

[0099] In some embodiments, prior to the administering, the fasting plasma insulin concentration in the individual is at least 25 mIU / L (at least 174 pmol / L).

[0100] In some embodiments, the administering increases the fasting plasma insulin concentration in the individual by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, or at least 10%. In some embodiments, the administering increases the fasting plasma insulin concentration in the individual within 6 months, within 5 months, within 4 months, within 3 months, within 2 months, or within 1WSGR Reference No.47535-754.601 month. In some embodiments, the administering does not induce hypoglycemia in the individual.

[0101] In some embodiments, provided herein is a method of increasing the concentration of c-peptide in an individual comprising administering to the individual a menin inhibitor. In some embodiments, provided herein is a method of improving glycemic control in an individual comprising administering a menin inhibitor to the individual, wherein the administering increases the concentration of c-peptide in the individual.

[0102] In some embodiments, prior to administering, the c-peptide concentration in the individual is below 1.0 ng / mL, or below 0.9 ng / mL, or below 0.8 ng / mL, or below 0.7 ng / mL, or below 0.6 ng / mL, or below 0.5 ng / mL.

[0103] In some embodiments, the administering increases the c-peptide concentration in the individual within 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 2 months, 3 months, or 6 months. In some embodiments, the administering increases the c-peptide concentration to the range of about 0.5 to 2.0 ng / mL, or to within the range of about 0.9 to 1.8 ng / mL, or increases the c-peptide concentration by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%.

[0104] In some embodiments, the administering increases proliferation of islet β-cells. In some embodiments, the administering increases proliferation of islet β-cells and does not significantly increase proliferation of other cells. In some embodiments, the administering increases proliferation of islet β-cells by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, or 100%.

[0105] Clinical activity of the methods described herein may be evaluated according to any one of the measures described herein, or a combination thereof.

[0106] In some embodiments, the individual is pre-diabetic. In some embodiments, the individual has been diagnosed with diabetes. In some embodiments, the diabetes is type 1 diabetes. In some embodiments, the diabetes is type 2 diabetes. In some embodiments, the diabetes is gestational diabetes. In some embodiments, the individual exhibits prominent insulin resistance and / or defective pancreatic insulin secretion. In some embodiments, the individual has cardiovascular disease, optionally wherein the administering reduces the risk of major adverse cardiovascular events in the individual. In some embodiments, the individual has been diagnosed with diabetic heart disease.

[0107] In some embodiments, the individual to whom the menin inhibitor is administered according to the methods described herein has not been treated previously for the glycemic condition, e.g., diabetes. In some embodiments, the individual to whom the menin inhibitor is administered according to the methods described herein has not been treated previously for theWSGR Reference No.47535-754.601 glycemic condition, e.g., diabetes, and is newly diagnosed. In such embodiments, the administering of the menin inhibitor (alone or in combination with one or more combination agents) is a first-line therapy. In some embodiments, the individual has been treated previously for the glycemic condition. In some embodiments, the prior treatment is a glucagon-like peptide-1 (GLP1) receptor agonist (e.g., tirzepatide, lixisenatide, exenatide, semaglutide, albiglutide, dulaglutide, or liraglutide), an antihyperglycemic agent, insulin (e.g., administered by syringe, insulin pen, or insulin pump; e.g., pre-mixed, rapid-acting, ultra rapid-acting, inhaled, short-acting, intermediate-acting, or ultra long-acting, or a combination) or an insulin derivative, an insulin secretagogue, an SGLT2 inhibitor (e.g., dapagliflozin, canagliflozin, empagliflozin, or ertugliflozin), a meglitinide (e.g., repaglinide or nateglinide), a dipeptidyl peptidase IV (DPP-4) inhibitor (e.g., sitagliptin, saxagliptin, alogliptin, or linagliptin), a sulfonylurea (e.g., glimerpiride, glyburide, chlorpropamide, glipizide, tolbutamide, or tolazamide), a biguanide (e.g., metformin), a PPAR agonist (e.g., a PPAR-gamma agonist) such as a thiazolidinedione (e.g., pioglitazone or rosiglitazone), a bile acid sequestrant (e.g., colesevelam), an alpha-glucosidase inhibitor (e.g., miglitol or acarbose), a dopamine receptor agonist (e.g., bromocriptine), or an amylin mimetic (e.g., pramlintide acetate), or a combination thereof (e.g., metformin and pioglitazone, rosiglitazone, glyburide, canagliflozin, sitagliptin, linagliptin, alogliptin, saxagliptin, glipizide, repaglinide, or dapagliflozin; glimerpiride and rosiglitazone or pioglitazone; empagliflozin and linagliptin; alogliptin and pioglitazone), or a combination thereof. For example, in some embodiments, the individual has been treated previously with metformin, optionally in combination with an SGLT2 inhibitor or a GLP-1 receptor agonist. In some embodiments, the individual has been diagnosed with type 2 diabetes and has been treated with metformin, optionally in combination with an SGLT2 inhibitor or a GLP-1 receptor agonist. In some embodiments, the individual has been treated previously with a combination of metformin plus a DPP-4 inhibitor or a GLP-1 receptor agonist plus an SGLT2 inhibitor or thiazolidinedione, e.g., Trijardy XR (empagliflozin, linagliptin, and metformin hydrochloride) or Qternmet XR (dapagliflozin, saxagliptin, and metformin), optionally wherein the individual has been diagnosed with type 2 diabetes. In some embodiments, the individual has been treated with pioglitazone, a sulfonylurea, a glinide, insulin, a DPP-4 inhibitor, or acarbose, or a combination. In some embodiments, the individual has been diagnosed with type 1 diabetes, and has been treated with insulin or an insulin derivative. In some embodiments, the individual has been treated with β-cell replacement therapy. In some embodiments, the β-cell replacement therapy comprises transplant of pancreatic cells, islet cells, β-cells, or the pancreas, or comprises stem cell therapy using, for example, human embryonic stem cells or induced pluripotent stem cells, or comprises enhancement of β-cell replication or formation of new islets.WSGR Reference No.47535-754.601 In some embodiments, the therapy comprises transplant of pancreatic islet cells, optionally where the cells are stem cell-derived, fully differentiated pancreatic islet cells, optionally VX- 880 (Vertex). In some embodiments, the β-cell replacement therapy comprises implantation of pancreatic precursor cells, such as device-encapsulated pancreatic precursor cells (e.g., PEC- Direct or VC-02 (ViaCyte) (NCT03163511). In some embodiments, the therapy comprises islet cell replacement therapy, optionally using allogeneic pancreatic endocrine cell clusters (e.g., SR- 02 (Seraxis). In some embodiments, the individual has been treated with one prior therapy, and the administering of the menin inhibitor (alone or in combination with one or more combination agents) is a second-line therapy. As used herein, a “line” of treatment is a course of treatment with a particular therapy or combination of therapies. In some embodiments, the menin inhibitor is administered as part of a first-line therapy. In some embodiments, the menin inhibitor is administered as part of a second or subsequent line of therapy.

[0108] In some embodiments, the administering does not produce a significant toxicity or does not produce a significant risk of one or more adverse events, optionally wherein the one or more adverse events are selected from neutropenia, thrombocytopenia, QTc prolongation, adverse cardiovascular event, differentiation syndrome, or tumor lysis syndrome. In some embodiments, the administering: (a) reduces the risk of one or more adverse cardiac events in the individual, optionally wherein the one or more adverse events are selected from developing cardiovascular disease, worsening cardiovascular disease, major adverse cardiovascular event in an individual with cardiovascular disease, death from cardiovascular causes, myocardial infarction (optionally wherein the myocardial infarction is a non-fatal myocardial infarction), stroke (optionally wherein the stroke is a non-fatal stroke); or (b) provides cardiac protection to the individual. In some embodiments, the administering provides a lower risk of QTc prolongation. In some embodiments, the administering provides a lower risk of neutropenia or thrombocytopenia. In some embodiments, the administering provides a lower risk of differentiation syndrome or of tumor lysis syndrome. In some embodiments, the lower risk is for the menin inhibitor, for example, ziftomenib, compared to one or more other menin inhibitors or one or more other pharmaceutical treatments (such as one or more of the treatments listed herein as combination agents).

[0109] In some embodiments, the menin inhibitor, such as ziftomenib, provides greater clinical activity than other menin inhibitors or than alternative therapies. In some embodiments, the menin inhibitor is ziftomenib and the safety profile is preferable to the safety profile of other menin inhibitors or of alternative therapies.WSGR Reference No.47535-754.601 Therapeutic Combinations

[0110] In certain embodiments, the menin inhibitor may be administered to an individual in combination with a combination agent. In some embodiments, the combination agent comprises an antidiabetic agent or an agent indicated for improving glycemic control or other symptoms or characteristics of diabetes. In some embodiments, the combination agent comprises a glucagon- like peptide-1 (GLP-1) receptor agonist (e.g., tirzepatide, lixisenatide, exenatide, semaglutide, albiglutide, dulaglutide, or liraglutide), an antihyperglycemic agent, insulin (e.g., administered by syringe, insulin pen, or insulin pump; e.g., pre-mixed, rapid-acting, ultra rapid-acting, inhaled, short-acting, intermediate-acting, or ultra long-acting, or a combination) or an insulin derivative, an insulin secretagogue, an SGLT2 inhibitor (e.g., dapagliflozin, canagliflozin, empagliflozin, or ertugliflozin), a meglitinide (e.g., repaglinide or nateglinide), a dipeptidyl peptidase IV (DPP-4) inhibitor (e.g., sitagliptin, saxagliptin, alogliptin, or linagliptin), a sulfonylurea (e.g., glimerpiride, glyburide, chlorpropamide, glipizide, tolbutamide, or tolazamide), a biguanide (e.g., metformin), a PPAR agonist (e.g., a PPAR-gamma agonist) such as a thiazolidinedione (e.g., pioglitazone or rosiglitazone), a thiazolidinedione (e.g., pioglitazone or rosiglitazone), a bile acid sequestrant (e.g., colesevelam), an alpha-glucosidase inhibitor (e.g., miglitol or acarbose), a dopamine receptor agonist (e.g., bromocriptine), an activin type II receptor blocker (e.g., monoclonal antibody, bimagrumab), or an amylin mimetic (e.g., pramlintide acetate, cagrilintide), or a combination (e.g., metformin and pioglitazone, rosiglitazone, glyburide, canagliflozin, sitagliptin, linagliptin, alogliptin, saxagliptin, glipizide, repaglinide, or dapagliflozin; glimerpiride and rosiglitazone or pioglitazone; empagliflozin and linagliptin; alogliptin and pioglitazone). In some embodiments, the combination agent comprises metformin (e.g., metformin hydrochloride), semaglutide, liraglutide, sitagliptin, exenatide, insulin glargine, a sulfonylurea, thiazolidinedione, pioglitazone, or insulin, or a combination thereof. In some embodiments, the combination agent is metformin, an SGLT2 inhibitor, or a GLP-1 receptor agonist, or a combination thereof. In some embodiments, the individual has been diagnosed with type 2 diabetes and the combination agent is metformin, an SGLT2 inhibitor, or a GLP-1 receptor agonist, or a combination thereof. In some embodiments, the combination agent is pioglitazone, a sulfonylurea, a glinide, insulin, a DPP-4 inhibitor, or acarbose, or a combination thereof. In some embodiments, the individual has been diagnosed with type 1 diabetes, and the combination agent is insulin or an insulin derivative. In some embodiments, the combination agent is a GLP1-R agonist (e.g., tirzepatide, lixisenatide, exenatide, semaglutide, albiglutide, dulaglutide, or liraglutide). In some embodiments, the combination agent is a PPAR agonist (e.g., a PPAR-gamma agonist) such as a thiazolidinedione (e.g., pioglitazone or rosiglitazone). In some embodiments, the combination agent is aWSGR Reference No.47535-754.601 combination of metformin plus a DPP-4 inhibitor or a GLP-1 receptor agonist plus an SGLT2 inhibitor or thiazolidinedione, e.g., Trijardy XR (empagliflozin, linagliptin, and metformin hydrochloride) or Qternmet XR (dapagliflozin, saxagliptin, and metformin), optionally wherein the individual has been diagnosed with type 2 diabetes. In some embodiments, the menin inhibitor is administered as an adjunct to diet and / or exercise.

[0111] As shown herein, menin inhibitors such as ziftomenib have been found to stimulate β- cell proliferation, indicating potential utility in treating diabetic patients (such as type 1 diabetes) in combination with β-cell replacement therapy or to increase β-cell mass in diabetic patients with depleted β-cell mass. In other embodiments, the menin inhibitor is administered in combination with a β-cell replacement therapy or other therapy that aims to restore insulin production in the pancreas. In some embodiments, this combination is for a method of treating an individual with type 1 diabetes. In some embodiments, the β-cell replacement therapy comprises transplant of pancreatic cells, islet cells, β-cells, or the pancreas, or comprises stem cell therapy using, for example, human embryonic stem cells or induced pluripotent stem cells, or comprises enhancement of β-cell replication or formation of new islets. In some embodiments, the therapy comprises transplant of pancreatic islet cells, optionally where the cells are stem cell-derived, fully differentiated pancreatic islet cells, optionally VX-880 (Vertex). In some embodiments, the β-cell replacement therapy comprises implantation of pancreatic precursor cells, such as device-encapsulated pancreatic precursor cells (e.g., PEC- Direct or VC-02 (ViaCyte) (NCT03163511). In some embodiments, the therapy comprises islet cell replacement therapy, optionally using allogeneic pancreatic endocrine cell clusters (e.g., SR- 02 (Seraxis).

[0112] For therapeutic combinations, dosages, treatment regimens, and effective amounts of each administered agent may vary depending on the severity of the disease, the age and relative health of the subject, the potency of the compound(s) used and other factors. In some embodiments, the individual is already taking a combination agent, and the menin inhibitor is added to the dosing regimen. In some embodiments, the individual initiates treatment with both the menin inhibitor and the combination agent at the same time or at approximately the same time. Pharmaceutical Compositions

[0113] In some embodiments, provided herein is a pharmaceutical composition comprising a menin inhibitor, such as ziftomenib or a pharmaceutically acceptable form thereof, and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises ziftomenib or a pharmaceutically acceptable salt thereof, or a solvate thereof. InWSGR Reference No.47535-754.601 some embodiments, the methods provided herein comprise administering such pharmaceutical compositions.

[0114] Pharmaceutical compounds are formulated according to several factors well within the purview of those of ordinary skill in the art. These include, without limitation: the type and nature of the active agent being formulated; the subject to which the agent-containing composition is to be administered; the intended route of administration of the composition; and the therapeutic indication being targeted.

[0115] The pharmaceutical compositions are intended to be administered by a suitable route, including but not limited to orally, parenterally, rectally, topically, locally, intradermally, intramuscularly, intraperitoneally, percutaneously, intravenously, subcutaneously, intranasally, epidurally, sublingually, intracerebrally, intravaginally, transdermally, mucosally, by inhalation, or topically to the ears, nose, eyes, or skin. The pharmaceutical compositions are in liquid, semi-liquid or solid form and are formulated in a manner suitable for each route of administration. In some embodiments, the pharmaceutical compositions provided herein are administered orally. For oral administration, capsules and tablets can be formulated.

[0116] In some embodiments, the pharmaceutical compositions are provided for administration to a subject in dosage forms such as tablets, capsules, microcapsules, pills, powders, granules, troches, suppositories, injections, syrups, patches, creams, lotions, ointments, gels, sprays, sterile parenteral solutions or suspensions, and oral solutions or suspensions, and oil water emulsions containing suitable quantities of the compounds or pharmaceutically acceptable forms thereof. In some embodiments, the pharmaceutical compositions provided herein are in the form of a tablet. In some embodiments, the pharmaceutical compositions provided herein are in the form of a capsule. Kits

[0117] For use in the therapeutic applications described herein, kits and articles of manufacture are also provided. In some embodiments, such kits comprise a carrier, package, or container that is compartmentalized to receive one or more containers such as vials, tubes, and the like, each of the container(s) comprising one of the separate elements to be used in a method described herein. Suitable containers include, for example, bottles, vials, syringes, and test tubes. The containers are formed from a variety of materials such as glass or plastic.

[0118] In yet another aspect, the present disclosure provides a kit comprising an effective amount of a pharmaceutical composition comprising a menin inhibitor and a pharmaceutically acceptable carrier or excipient, in a dosage form.WSGR Reference No.47535-754.601

[0119] The articles of manufacture provided herein contain packaging materials. Packaging materials for use in packaging pharmaceutical products include those found in, e.g., U.S. Pat. Nos.5,323,907, 5,052,558 and 5,033,252. Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, bottles, and any packaging material suitable for a selected formulation and intended mode of administration and treatment. For example, the container(s) includes a menin inhibitor (e.g., ziftomenib), or a pharmaceutically acceptable form thereof, optionally in a composition or in combination with a combination agent as disclosed herein. The container(s) optionally have a sterile access port (for example the container is an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle). Such kits optionally comprising a compound with an identifying description or label or instructions relating to its use in the methods described herein.

[0120] For example, a kit typically includes one or more additional containers, each with one or more of various materials (such as reagents, optionally in concentrated form, and / or devices) desirable from a commercial and user standpoint for use of a compound described herein. Non- limiting examples of such materials include, but not limited to, buffers, diluents, filters, needles, syringes; carrier, package, container, vial and / or tube labels listing contents and / or instructions for use, and package inserts with instructions for use. A set of instructions will also typically be included. A label is optionally on or associated with the container. For example, a label is on a container when letters, numbers or other characters forming the label are attached, molded, or etched into the container itself, a label is associated with a container when it is present within a receptacle or carrier that also holds the container, e.g., as a package insert. In addition, a label is used to indicate that the contents are to be used for a specific therapeutic application. In addition, the label indicates directions for use of the contents, such as in the methods described herein. In certain embodiments, the pharmaceutical composition is presented in a pack or dispenser device which contains one or more unit dosage forms containing a compound provided herein. The pack, for example, contains metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration. The pack or dispenser may be accompanied by a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration. Such notice, for example, is the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the approved product insert. In some embodiments, compositions containing a compound provided herein formulated in a compatibleWSGR Reference No.47535-754.601 pharmaceutical carrier are prepared, placed in an appropriate container, and labeled for treatment of an indicated condition. Definitions

[0121] Compounds of the present disclosure also include crystalline and amorphous forms of those compounds, pharmaceutically acceptable salts, and active metabolites of these compounds having the same type of activity, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of the compounds, as well as mixtures thereof.

[0122] As used herein, a “pharmaceutically acceptable form” of a compound disclosed herein includes a tautomer, stereoisomer, mixture of stereoisomers, or racemic mixture thereof, or an isotopologue thereof, a pharmaceutically acceptable salt of any of the preceding forms, or a solvate of any of the preceding forms. In some embodiments, ziftomenib or a “pharmaceutically acceptable form” thereof includes, but is not limited to, ziftomenib or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0123] The compounds described herein may exhibit their natural isotopic abundance, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure. For example, hydrogen has three naturally occurring isotopes, denoted(protium),2H (deuterium), and3H (tritium). Protium is the most abundant isotope of hydrogen in nature. Enriching for deuterium may afford certain therapeutic advantages, such as increased in vivo half-life and / or exposure, or may provide a compound useful for investigating in vivo routes of drug elimination and metabolism. Isotopically enriched compounds may be prepared by conventional techniques well known to those skilled in the art.

[0124] The term “isotopolog” refers to an isotopically enriched compound. The term “isotopically enriched” refers to an atom having an isotopic composition other than the natural isotopic composition of that atom. “Isotopolog” can also refer to a compound containing at least one atom having an isotopic composition other than the natural isotopic composition of that atom. The term “isotopic composition” refers to the amount of each isotope present for a given atom. Radiolabeled and isotopically enriched compounds are useful as therapeutic agents, e.g., diabetes therapy agents, research reagents, e.g., binding assay reagents, and diagnostic agents, e.g., in vivo imaging agents. All isotopic variations of the compounds described herein, whetherWSGR Reference No.47535-754.601 radioactive or not, are intended to be encompassed within the scope of the embodiments provided herein.

[0125] “Isomers” are different compounds that have the same molecular formula. “Stereoisomers” are isomers that differ only in the way the atoms are arranged in space. “Enantiomers” are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a “racemic” mixture. The term “(±)” is used to designate a racemic mixture where appropriate. “Diastereoisomers” or “diastereomers” include stereoisomers that have at least two asymmetric atoms but are not mirror images of each other. The absolute stereochemistry is specified according to the Cahn-Ingold-Prelog R-S system. When a compound is a pure enantiomer, the stereochemistry at each chiral carbon can be specified by either R or S. Resolved compounds whose absolute configuration is unknown can be designated (+) or (-) depending on the direction (dextro- or levorotatory) in which they rotate plane polarized light at the wavelength of the sodium D line. Certain compounds described herein contain one or more asymmetric centers and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms, the asymmetric centers of which can be defined, in terms of absolute stereochemistry, as (R)- or (S)-. The present chemical entities, pharmaceutical compositions and methods are meant to include all such possible stereoisomers, including racemic mixtures, optically pure forms, mixtures of diastereomers and intermediate mixtures. Optically active (R)- and (S)-isomers can be prepared using chiral synthons or chiral reagents or can be resolved using conventional techniques. The optical activity of a compound can be analyzed via any suitable method, including but not limited to chiral chromatography and polarimetry, and the degree of predominance of one stereoisomer over the other isomer can be determined.

[0126] Chemical entities having carbon-carbon double bonds or carbon-nitrogen double bonds may exist in Z- or E- form (or cis- or trans- form). Furthermore, some chemical entities may exist in various tautomeric forms. Unless otherwise specified, chemical entities described herein are intended to include all Z-, E- and tautomeric forms as well.

[0127] The term “solvate” generally refers to a compound (e.g., free base) or a salt thereof, that further includes a stoichiometric or non-stoichiometric amount of solvent bound by non- covalent intermolecular forces. Wherein the solvent is water, the solvate is a hydrate.

[0128] The term “salt” or “pharmaceutically acceptable salt” refers to salts derived from a variety of organic and inorganic counter ions well known in the art. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts canWSGR Reference No.47535-754.601 be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salt is chosen from ammonium, potassium, sodium, calcium, and magnesium salts.

[0129] The term “pharmaceutical composition” generally refers to a composition comprising a therapeutic agent and a pharmaceutically acceptable excipient. A “pharmaceutically acceptable excipient” refers to media generally accepted in the art for the delivery of biologically active agents to an individual, including, e.g., adjuvants, vehicles, diluents, preserving agents, fillers, flow regulating agents, disintegrating agents, wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents, perfuming agents, antibacterial agents, antifungal agents, lubricating agents and dispensing agents, depending on the nature of the mode of administration and dosage forms. Suitable carriers include without limitation any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye, colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier which has been approved by the United States Food and Drug Administration as being acceptable for use in humans or domestic animals. Descriptions of suitable pharmaceutically acceptable excipients, and factors involved in their selection, are found in a variety of readily available sources such as, for example, Allen, L. V., Jr. et al., Remington: The Science and Practice of Pharmacy (2 Volumes), 22nd Edition, Pharmaceutical Press (2012).

[0130] As used herein, “treatment” or “treating” refers to an approach for obtaining beneficial or desired results with respect to a disease, disorder, or medical condition (e.g., diabetes) including but, in certain instances, not limited to a therapeutic benefit and / or a prophylactic benefit. Therapeutic benefit refers to eradication or amelioration of the underlying disorder being treated. A therapeutic benefit is also achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the individual, notwithstanding that the individual may still beWSGR Reference No.47535-754.601 afflicted with the underlying disorder. In certain embodiments, for prophylactic benefit, the compositions are administered to an individual at risk of developing a particular disease, or to an individual reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made.

[0131] As used herein, the term “effective amount” in connection with a compound means an amount capable of treating, preventing, or managing a disorder, disease, or condition, or one or more symptoms thereof.

[0132] “Individual” refers to an animal, such as a mammal, for example a human. The methods described herein can be useful in both human therapeutics and veterinary applications. In some embodiments, the individual is a mammal, and in some embodiments, the individual is human. “Mammal” includes humans and both domestic animals such as laboratory animals and household pets (e.g., cats, dogs, swine, cattle, sheep, goats, horses, rabbits), and non-domestic animals such as wildlife and the like. In some embodiments, the human is ≥ 18 years of age. In some embodiments, the human is less than 18 years of age, less than 12 years of age, less than 6, 5, 4, 3, 2, or 1 year of age.

[0133] The term “%HbA1c” refers to the result of the hemoglobin A1C test, which is a blood test to measure average blood sugar levels over a period of time, e.g., 3 months in humans, as a function of the percentage of red blood cells that have sugar-coated hemoglobin. The %HbA1c for a normal (non-diabetic) individual is below 5.7%; a result in the range of 5.7 to 6.4% indicates pre-diabetes, and a result of 6.5% or higher indicates diabetes. As used herein, “elevated %HbA1c” is a level of at least 5.7%.

[0134] The term “pp” as used herein refers to percentage points. For example, a reduction from 7% to 5% represents a reduction in 2pp.

[0135] As used herein, “fasting blood glucose” or FBG, also referred to as “fasting plasma glucose” or FPG, is the fasting blood glucose concentration. The concentration is determined by taking a blood sample from an individual who has fasted for at least 8 hours. Results are reported in mmol / L or in mg / dL. Normal FBG concentrations for humans are between 70 mg / dL (3.9 mmol / L) and 100 mg / dL (5.6 mmol / L). An “elevated” FBG concentration is above 100 mg / dL (5.6 mmol / L). A level from 100 to 125 mg / dL (5.6 to 6.9 mmol / L) indicates pre- diabetes and a level of 126 mg / dL (7 mmol / L) or higher indicates diabetes in the individual.

[0136] As used herein, “postprandial glucose concentration” is the blood glucose concentration measured shortly (e.g., 2 hours) after a meal, such as a high carbohydrate meal using an oral glucose tolerance test. Following a meal, insulin and blood glucose levels increase, but should return to normal within a short time after the meal. If glucose levels remain high, the tested individual may be diabetic or pre-diabetic. In humans, a postprandial glucoseWSGR Reference No.47535-754.601 concentration of less than 140 mg / dL is normal, a level of from 140 to 199 mg / dL indicates pre- diabetes or diabetes, and a level of at least 200 mg / dL indicates diabetes. Measurements may also be reported in mmol / L units.

[0137] As used herein, “HOMA-IR” (homeostatic model assessment of insulin resistance) is a calculated value that indicates the presence and extent of insulin resistance expressed by an individual. HOMA-IR is calculated according to, for example, one of the following formulae: (a) HOMA-IR = FBG (mmol / L) x fasting insulin level (mIU / L) / 22.5; or (b) HOMA-IR = glucose (mg / dL) x insulin (mU / mL). A HOMA-IR value of less than 1.0 indicates the individual is insulin-sensitive (non-diabetic); a value of above 1.9 indicates early insulin resistance; and a level above 2.9 indicates significant insulin resistance. The HOMA-IR value is a predictor of cardiovascular disease in T2D.

[0138] As used herein, “HOMA-B” (homeostasis model assessment of beta cell function) refers to a mathematical model that estimates how well the β-cells in the pancreas are producing insulin. The model uses fasting plasma glucose and insulin concentrations to calculate a percentage of β-cell function relative to a normal population. HOMA-B is calculated using the following formula: (20 x Fasting Insulin (µU / mL)) / (Fasting Glucose (mmol / L) – 3.5). A HOMA-B value of 100 to 200 is considered normal (non-diabetic). Increased HOMA-B values indicate greater β-cell dysfunction.

[0139] As used herein, “fasting plasma insulin” is the concentration of insulin in blood after fasting (e.g., 8-12 hours for humans, or e.g., 4 h for rodents) and is a measure of insulin insufficiency. Normally, insulin and blood glucose levels rise and fall together; after a meal, blood glucose levels rise and the pancreas releases more insulin into the blood. The insulin allows glucose to enter cells, thereby lowering blood glucose over time. Normal range for fasting insulin levels for humans is < 25 mIU / L (<174 pmol / L) and higher levels may indicate insulin resistance and may indicate diabetes. In rats, normal levels may be approximately 5 ng / mL.

[0140] C-peptide concentration (pmol / L) is tested by blood test after fasting. Normal range for this test in humans is 0.5 to 2.0 or 0.9 to 1.8 ng / mL (0.2 to 0.8 nmol / L). Lower levels may indicate the pancreas is producing little or no insulin (insulin insufficiency). An elevated level may indicate insulin resistance.

[0141] As used herein, “food intake” is the mass of food ingested by a test animal (or, as an average, for a group of test animals) over time, for example, over 24 h for a 24 h food intake measure, and may be measured in grams.WSGR Reference No.47535-754.601

[0142] As used herein, “water intake” is the mass of water ingested by a test animal (or, as an average, for a group of test animals) over time, for example, over 24 h for a 24 h water intake measure, and may be measured in grams.

[0143] As used herein, “body weight” is the mass of an individual, such as a human or a test animal, and may be measured in grams, kilograms, or pounds.

[0144] The terms “combination” or “administered in combination with” and their grammatical equivalents, as used herein, encompass administration of two or more agents to an animal, including humans, so that both agents and / or their metabolites are present in the individual at the same time. Two or more agents administered in combination may be administered on the same schedule or different schedules. Concomitant administration includes administration in separate compositions or administration in a composition in which both agents are present.

[0145] The term “inhibitor” refers to a compound having the ability to inhibit a biological function (e.g., activity, expression, binding, protein-protein interaction) of a target protein (e.g., menin, MLL1, MLL2, and / or an MLL fusion protein).

[0146] As used herein, a “sample” includes and / or refers to any fluid or liquid sample which is being analyzed in order to detect and / or quantify an analyte. In some embodiments, a sample is a biological sample. Examples of samples include without limitation a bodily fluid, an extract, a solution containing proteins and / or DNA, a cell extract, a cell lysate, or a tissue lysate. Non- limiting examples of bodily fluids include urine, saliva, blood, serum, plasma, cerebrospinal fluid, tears, semen, sweat, pleural effusion, liquified fecal matter, and lacrimal gland secretion.

[0147] The term “in vivo” refers to an event that takes place in an individual’s body.

[0148] The term “in vitro” refers to an event that takes places outside of an individual’s body. For example, an in vitro assay encompasses any assay run outside of an individual. In vitro assays encompass cell-based assays in which cells alive or dead are employed. In vitro assays also encompass a cell-free assay in which no intact cells are employed.

[0149] As used herein, “safety risk” refers to the risk of an individual suffering from one or more adverse events, such as a treatment-related or treatment-associated adverse event, or a severe treatment-related or treatment-associated adverse event (e.g., an event at greater than or equal to Grade 3 severity).

[0150] As used herein, the words “comprising” (and any form of comprising, such as “comprise” and “comprises”), “having” (and any form of having, such as “have” and “has”), “including” (and any form of including, such as “include” and “includes”) or “containing” (and any form of containing, such as “contain” and “contains”), are inclusive or open-ended and do not exclude additional, unrecited elements or process steps. As also used herein, in any instance or embodiment described herein, “comprising” may be replaced with “consisting essentially of”WSGR Reference No.47535-754.601 and / or “consisting of”. used herein, in any instance or embodiment described herein, “comprises” may be replaced with “consists essentially of” and / or “consists of”.

[0151] As used herein, the term “and / or” is to be taken as specific disclosure of each of the two specified features or components with or without the other. For example, “A and / or B” is to be taken as specific disclosure of each of (i) A, (ii) B, and (iii) A and B, just as if each were set out individually herein.

[0152] As used herein, the term “about,” when used in connection with doses, amounts, or weight percentages, mean a dose, amount, or weight percent within 10%, or within 5%, or within 2%, or within 1% of the stated amount.

[0153] Where a numerical value is used herein, such a value may encompass a range that is ± 5% of the stated numerical value. EXAMPLES

[0154] The following examples are included for illustrative purposes only and are not intended to limit the scope of the present disclosure. Example 1 – Study of Effects of Ziftomenib, BMF-219, and Semaglutide in Zucker Diabetic Fatty Male Rats (T2D Model)

[0155] Zucker diabetic fatty (ZDF) male rats (~ 350 g, 12-13 weeks; average FBG 23 mmol / L; Charles River, Beijing, China) were assigned to 4 groups (11 animals in each group) based on body weight and blood glucose (random blood glucose level (not fasted) > 11.1 mM). Animals were fed on a high calorie / high sugar diet (Beijing Keao Xieli Feed Co., Ltd., Cat. No. K5008). Dosing was performed daily for 27 days as follows: a) vehicle (5 mL / kg, PO, QD); b) ziftomenib (200 mg / kg, PO, QD, Days 1-10; 100 mg / kg, PO, QD, Days 11-27); c) semaglutide (6.25, 12.5, 25, or 50 nmol / kg in PBS solution; SC; Q3D; 4-step dose escalation, 6 days per step (Melander et al., Eur. J. Pharmacol.2023, 5(938), 175397); and d) BMF-219 (200 mg / kg, solution in 20% HP-β-CD, PO, QD). Body weights were recorded daily throughout the study. Ziftomenib dosing was reduced from 200 mg / kg to 100 mg / kg starting at Day 11 due to observed weight loss in animals dosed at 200 mg / kg.

[0156] Blood glucose levels were measured on Days 0, 6, 12, 21, and 27. Four-hour fasting glucose was measured by Glucometer through lateral tail vein sampling. Blood collection was done on Days 0, 6, 12, 21, and 27, after fasting rats for 4 h. Whole blood (WB; ~20 µL) was collected from the lateral tail vein for each animal and transferred into EDTA-2k tubes for %HbA1c level measurement, and ~80 µL WB samples were processed for plasma byWSGR Reference No.47535-754.601 centrifugation at 4 °C / 7000 rpm for 10 min, and the resulting pellet was stored at -80 °C for insulin analysis. HOMA-IR was calculated as described in Section 4 below.

[0157] At Day 27, all rats were dosed per the dose protocol in the morning before fasting, and 4 h-fasting glucose was then measured by tail vein. After measuring Day 27 BG, each group of animals was divided into three subgroups, distributed to provide comparable body weight and blood glucose characteristics across the groups. The animals were used for different termination operations as shown in Table 1. Table 1. Animals Treatment Oral Glucose Tolerance Test (OGTT) 5 Blood glucose level and insulin level measurements The tail of pancreas collection, liver, musclulus WB and RNA extraction 3 gastrocnemius, brown fat, perirenal fat, ~30 mg RNA tissue collection later for RNA extraction, ~30 mg flash frozen for WB The tail of pancreas, liver, musclulus gastrocnemius, IHC tissue collection 3 brown fat, perirenal fat, fixed in 10% neutral buffered formalin

[0158] Day 27 OGTT: Rats were placed in new cages at 9:00 am and fasted for 6 hours, and basal fasting glucose was measured by tail vein. Glucose was orally gavaged with 1.5 g / kg at a dose volume of 5 mL / kg. Blood glucose levels were measured at 15-, 30-, 60-, 120-min, and 180-min post glucose dosing. Blood samples (~60 µL) were processed at 15-, 30-, 60-, 120-min timepoints for plasma by centrifugation at 4 °C / 7000 rpm for 10 min, and stored at -80 °C for insulin analysis at each time point.

[0159] When animals were sacrificed, 10 mL of WB was collected per animal. 20 µL of WB was used for %HbA1c measurement, and the remaining WB was centrifuged at 3200 x g for 10 min to collect serum. The serum was aliquoted into tubes and stored at -80 ºC for biochemical assays. 100 µL of the serum was used to measure the serum c-peptide concentration.

[0160] WB and RNA extraction tissue collection: The tail of pancreas was dissected, and 2 chunks of ~30 mg each of dissected pancreas tail were soaked in RNAlater® (Thermo Fisher) overnight at 2-8 °C and then stored at -80 °C for RNA extraction. 2 chunks of ~30 mg each were flash-frozen and stored at -80 °C for other analyses such as western blot. Liver, musculus gastrocnemius, brown fat, and perirenal fat were collected and each specimen was divided into several chunks. 2 chunks / tissue were soaked in RNAlater® as described above and 2 chunks / tissue were flash-frozen as described above.

[0161] IHC tissue collection: Tissues were collected and fixed in 10% neutral buffered formalin (NBF) for further analysis.WSGR Reference No.47535-754.601

[0162] Ki67 staining: Formalin-fixed paraffin-embedded (FFPE) tissue slices were deparaffinized and rehydrated by treating with xylene and ethanol followed by the deionized water treatment. The antigen retrieval procedure was performed by soaking slides in 1 mM EDTA solution (in water) at 85-100 °C for 20 min. The samples were blocked in non-immune goat serum. Ki67 antibody was hybridized in goat serum for 1 h at 37 °C, followed by the secondary antibody hybridization. The stained slides were mounted and analyzed by a microscope.

[0163] Hematoxylin and eosin (H&E) staining: FFPE tissue slices were deparaffinized and rehydrated by treating with xylene and ethanol followed by deionized water. The slices were stained with hematoxylin for 10 min. The slices were washed in water for 5 min, in 1% HCl- alcohol for 4 sec, in water for 5 min, and in 80% ethanol for 1 min. Slices were further stained with eosin for 5 sec. The slices were washed in ethanol for 2 min x 5 and in xylene for 5 min x3. The slices were mounted and analyzed by a microscope.

[0164] TUNEL (TdT-mediated dUTP-biotin nick end labeling) staining: FFPE tissue slices were deparaffinized and rehydrated by treating with xylene and ethanol followed by deionized water. The slices were treated with Proteinase K at 37 °C for 30 min and washed in PBS thoroughly. A terminal deoxynucleotidyl transferase (TdT) reaction was performed at 37 °C for 60 min in the dark. The signals were visualized by streptavidin fluorescein. The samples were mounted in the mounting solution with DAPI, and analyzed by a microscope.

[0165] All statistics were determined using a two tailed t-test for significance unless otherwise specified. Example 1.1. – 4-Hour Fasting Blood Glucose Levels

[0166] Ziftomenib single agent treatment reduced 4 h FBG rapidly (within 7 days) and significantly throughout the study period compared to vehicle, semaglutide, and BMF-219 treatment (FIG.1; *, p<0.05; ***, p<0.005; ****, p<0.001)). Mean FBG levels for the ziftomenib group were reduced to close to 7 mmol / L by Day 27, and in several animals by Day 12.

[0167] Several animals treated with ziftomenib showed FBG levels normalized to approximately 7 mmol / L (healthy FBG level for rat) at Day 27 as shown in FIG.2 (*, p<0.05, unpaired t-test for ziftomenib vs. BMF-219; ****, p<0.0001, unpaired t-test for ziftomenib vs. semaglutide; ****; p<0.001, 2-way ANOVA comparison to vehicle) and the extent of reduction at Day 27 was consistent across all animals in the ziftomenib group (FIG.3). Animals shown in lines with open circles had dosing holidays for Days 5-9 due to decreased food and water intake. The FBG levels immediately decreased after dosing was resumed at 100 mg / kg in these animals,WSGR Reference No.47535-754.601 indicating that the 100 mg / kg dose was effective. The 100 mg / kg dose was well-tolerated. In contrast, as shown in FIG.2 and FIG.4, 3 of the BMF-219-treated animals did not show a significant reduction in FBG at Day 27, as indicated by the dots above the bar in the BMF-219 lane in FIG.2 and the solid lines with open circles in FIG.4, suggesting that the FBG response to BMF-219 is variable across animals. Reduction in FBG at Day 27 in the ziftomenib group was statistically significantly lower than reductions induced by semaglutide over the same period. Example 1.2. – Water Intake, Food Intake, and Weight Change

[0168] Water intake for ziftomenib-treated animals was reduced compared to vehicle animals, as their blood glucose levels were almost normalized (animals with lower blood glucose levels do not need to flush glucose by drinking), while water intake of BMF-219-treated animals was continuously reduced throughout the study (FIG.5; data presented as mean ± SEM; 2-way ANOVA followed by Dunnett test by Prism GraphPad, n=11). Water intake in semaglutide- treated animals was reduced for a day following administration of each Q3D dose.

[0169] Food intake for ziftomenib-treated animals was reduced initially during treatment, while dosing at 200 mg / kg, but increased slightly throughout the rest of the study, while dosing at 100 mg / kg, while food intake for BMF-219-treated animals was continuously reduced throughout the study (FIG.6; data presented as mean ± SEM; 2-way ANOVA followed by Dunnett test by Prism GraphPad; n=11). Food intake in semaglutide-treated animals was reduced for a day following administration of each Q3D dose.

[0170] Animals dosed with ziftomenib showed initial weight loss (while dosing at 200 mg / kg) followed by recovery by Day 27 (period of dosing at 100 mg / kg), while the significant reduction in food and water intake for BMF-219-treated animals resulted in significant progressive weight loss throughout the study, which may be indicative of toxicity (FIG.7; data presented as mean ± SEM; 2-way ANOVA followed by Dunnett test by Prism GraphPad; n=11). Body weight for semaglutide-treated animals oscillated consistently with the variable food and water intake following each dose. Example 1.3. – Effects on %HbA1c

[0171] %HbA1c was measured on Days 6, 12, 21, and 27 (FIG.8; *, p<0.05; ***, p<0.005; ****, p<0.001). Ziftomenib reduced %HbA1c significantly, by approximately 1.5 percentage points and approaching the 4.7% threshold (representing healthy level for rat), at Day 27 compared to Day 0, while BMF-219 did not show a reduction relative to baseline and only limited the increase of %HbA1c compared to that observed in vehicle-treated animals. TheWSGR Reference No.47535-754.601 %HbA1c of ziftomenib-treated animals on Day 27 was significantly lower than the %HbA1c of BMF-219 treated animals. Example 1.4. – Efficacy in Oral Glucose Tolerance Test (OGTT)

[0172] An OGTT was performed on Day 27 using 5 animals / group after 6 h of fasting. During the glucose challenge, ziftomenib-treated animals showed significantly reduced glucose levels, comparable to the response for healthy rats, compared with vehicle- or BMF-219-treated animals (FIG.9; ns, not significant; **, p<0.01; ***, p<0.005; ****, p<0.001). In addition, ziftomenib-treated animals responded in a consistent fashion, while BMF-219 results were variable. AUC levels for the ziftomenib group also were significantly lower than the other test groups (FIG.10; *, p<0.05; **, p<0.01; ***, p<0.005; ****, p<0.001). Example 1.5. – Effects on Insulin Resistance

[0173] HOMA-IR, a measure of insulin resistance, was calculated using the 4 h FBG and insulin levels on Days 6, 12, 21, and 27 according to the following equation: HOMA-IR = FBG (mmol / L) x fasting insulin level (mIU / L) / 22.5. Results are shown in FIG.11 (*, p<0.05; **, p<0.01; ****, p<0.001). ZDF rats exhibit a significantly elevated HOMA-IR (e.g., 100 to 400) compared to healthy rats (approx.5). Ziftomenib-treated animals showed a significant reduction in HOMA-IR within a week and maintained low HOMA-IR throughout the study. HOMA-IR for these animals increased toward the end of the study due to increased insulin levels. Animals treated with BMF-219 showed a reduction that took longer to appear, and the reduction over time may be due to a reduction in insulin levels driven by reduced food and water intake in these animals over time. This suggests that ziftomenib re-sensitized animals to insulin significantly, and more rapidly than BMF-219. Example 1.6. – Ziftomenib Stimulates Insulin Production (Insulin Insufficiency)

[0174] Animals treated with ziftomenib showed significantly higher serum insulin concentration levels at Day 27 relative to the other 3 groups (FIG.12A; ****, p<0.001) with potential relevance to diabetic insulin insufficiency. Despite the increased insulin level, no hypoglycemia was observed in these animals. HOMA-B (FIG.12B; *, p<0.05; **, p<0.01; ***, p<0.005; ****, p<0.001), a measure of steady-state β-cell function, was calculated according to the following formula: (20 x Fasting Insulin (µU / mL)) / (Fasting Glucose (mmol / L) – 3.5). Ziftomenib significantly improved these values, suggesting improvement to steady-state β-cell function, while both semaglutide and BMF-219 exhibited only modest effects. c-Peptide concentration in ziftomenib-treated animals were increased at Day 27 as well,WSGR Reference No.47535-754.601 suggesting the increase in insulin levels for this group derived from the increased production of insulin in the pancreas, possibly due to β-cell restoration (FIG.13; ns, not significant; ***, p<0.005). Notably, BMF-219 did not induce an increase in insulin levels or a significant change in c-peptide relative to vehicle, even at Day 27. Of note, previous reports indicated that BMF- 219 did not exert any significant change to 4-h fasting insulin levels until at least Day 29 and then only at certain doses (see Somanath et al., Poster presented at ADA 2022, Abstract 113-LB, Diabetes 2022, 71 (Suppl 1), 113-LB; Somanath et al., Presentation #590, EASD Annual Meeting, September 2022). For Type 1 diabetes, producing an increase in insulin production may be warranted.

[0175] In sum, the two main pathologies of type 2 diabetes, insulin resistance (measured by HOMA-IR) and insulin insufficiency (e.g., declined pancreatic β-cell function; measured by HOMA-B) were positively affected by treatment of ZDF rats with ziftomenib. Example 1.7. – Pharmacokinetics of Ziftomenib in ZDF Rats

[0176] Both the 100 mg / kg and 200 mg / kg doses of ziftomenib produced similar Cmax levels in plasma within 6-8 hours of dosing, and plasma concentrations at or near the Cmax level were durable out to at least 24 h for the 100 mg / kg dose, and out to at least 48 h for the 200 mg / kg dose (FIG.14). Example 1.8. – Histopathology Results of Livers

[0177] In the ziftomenib-treated animals, no meaningful cell death was observed, as indicated by % TUNEL-positive cells (Table 2), and proliferation of hepatocytes was not observed, as indicated by % positive Ki67 cells (Table 3). No meaningful increase in necrosis, and no effects of steatosis, ballooning, inflammation, or fibroses were indicated in the ziftomenib group. Table 2. Ki67 and TUNEL IHC quantification results IHC slsllGroupslle ec 7 6islleC7 K leCL Esl6liKev ClL E NeCeitlvisatN U o UT atitosoisoP llT T % T P %ecVehicle 466970 368 0.079 438494 1611 0.367 Ziftomenib 834834 11118 1.332 770837 6441 0.836 Semaglutide 403230 234 0.058 331459 1593 0.481 BMF-219 365031 276 0.076 523257 1536 0.29WSGR Reference No.47535-754.601 Table 3. H&E staining quantification results Group ytn ）isotsa g %nieasldlismni s（serleleo n t m oisisA）²Cca a ooe) ror lmln tlfllc atatanabi eo m oeS%( IB F N T （ T M Vehicle 0 0 0 0 / 121.99 184609 1513.35 Ziftomenib 0 1 0 0 2 202.92 414245 2041.47 Semaglutid e 1 0 1 0 / 112.49 246910 2194.91 BMF-219 0 0 0 0 / 66.76 236997 3550.21

[0178] In summary, in the ZDF rat study, ziftomenib reduced blood glucose levels significantly, nearly to normalized levels in many treated animals. The decrease occurred rapidly, indicating that the mechanism of action is related to the improvement in insulin sensitivity (resistance). Ziftomenib did not induce major toxicity issues during the study at 100 mg / kg. Ziftomenib induced insulin production after about two weeks of continuous administration. Ziftomenib effects on blood glucose and insulin production were significantly superior to BMF-219.

[0179] Menin inhibitors have been shown to induce beta-cell proliferation in human pancreas (see PCT Pat. Appl. Publ. Nos. WO2018 / 106818 and WO2018 / 106820). The mechanistic connection was demonstrated as MEN1 deletion in db / db T2D mouse restored beta-cell proliferation and induced significant improvement in glucose tolerance (Yang et al., PNAS 2010). Beta-cell proliferation effects are a known effect of menin inhibition, as it is related to MEN1 (insulin insufficiency). However, here, ziftomenib surprisingly produced a range of effects related to insulin insufficiency, with a rapid onset that was too brief for the results to have been the result of the known beta-cell-based mechanism, and also surprisingly produced beneficial effects on several measures of insulin sensitivity that are unrelated to the previously reported mechanism. Example 2 – Study of Menin Inhibitors in Mouse and Rat Models

[0180] The effects of one or more of revumenib, VTP-50469, JNJ-75276617 (bleximenib), DS-1594, DS-1594a, DS-1594b, DSP-5336, MI-3454, M-808, A300-105A, BN104, CompoundWSGR Reference No.47535-754.601 A, Compound B1, Compound B2, Compound C, and other menin inhibitors in a db / db mouse model of T2D and obesity, a ZDF male rat model, a diet-induced obesity (DIO) mouse model, and a DIO rat model are conducted. Glycemic markers (reduction in fasting blood glucose level, %HbA1c, and other markers), HOMA-IR, and insulin secretion / β-cell proliferation are evaluated. Body weight and food and water intake are assessed. Histology of key organs are evaluated to assess mechanism of action. Minimum effective doses are determined and various dosing schedules are evaluated.

[0181] Example 2.1: In the db / db mouse model described in Example 1 (ave. FBG 18-20 mmol / L), animals were dosed with vehicle, ziftomenib (100 mg / kg, PO, QD), semaglutide (10 nmol / kg, SC, QD), or revumenib (50 mg / kg, PO, BID) for 28 days and evaluations continued from day 29 to day 56 (wash-out period). FBG and fasting insulin levels were evaluated on days 0, 6, 12, 21, and 27, and during the wash-out period on days 35, 42, 49, and 56. All test articles showed significantly reduced FBG levels (FIG.15A) at day 14, with greater reductions for the ziftomenib and semaglutide groups. FBG below baseline was maintained in the ziftomenib- treated group out to day 56, but in the semaglutide group, FBG rose by day 35 to the vehicle level, and in the revumenib group, FBG returned to the day 0 baseline level by day 28 and increased above that level by day 56. Four-hour fasting insulin levels (FIG.15B) increased modestly and significantly in the revumenib and ziftomenib groups, respectively, and then dropped over time in both groups during the wash-out period but remained above baseline at day 56. These results provide further indication that menin inhibition elevates insulin production by stimulating β-cell proliferation and expanding β-cell mass, and demonstrate a durable effect of menin inhibition on insulin levels. Analogously, C-peptide levels (FIG.15C) increased relative to vehicle in the ziftomenib and revumenib groups, with gains maintained out to day 56 (the end of the 4-week wash-out period). In contrast, semaglutide induced small increases in fasting insulin at days 6 and 14 (consistent with its GLP-1 receptor agonist activity through which insulin production in pancreatic β-cells is stimulated), but levels dropped quickly to baseline once dosing was halted. These results support clinical investigation of menin inhibitors such as ziftomenib or revumenib in heavily progressed diabetic patients with depleted β-cell mass (e.g., type 2 diabetes patients or patients who require insulin injections), or in combination with β-cell replacement therapies (e.g., in type 1 diabetes patients) as a way to stimulate β-cell proliferation in implanted β-cells.

[0182] Example 2.2: In another study with the db / db mouse model described in Example 1 (ave. FBG 25.8 mmol / L), animals were dosed with vehicle, ziftomenib (100 mg / kg, PO, QD), bleximenib (100 mg / kg, PO, QD), or semaglutide (10 nmol / kg, SC, QD) for 35 days. Ziftomenib and bleximenib both produced FBG reductions similar to those described inWSGR Reference No.47535-754.601 Examples 1 and 2.1, with significant reductions relative to vehicle by day 35 (FIG.16). For the ziftomenib group, FBG levels were maintained below vehicle levels throughout the dosing period. Example 3 – Effects of Menin Inhibitors in Combination

[0183] The effects of menin inhibitors in combination with approved diabetes medications such as metformin and semaglutide are evaluated as described above in ZDF rats, db / db mice, DIO mice, and DIO rats. Example 4 – Organoid Model of Human Pancreatic Islets

[0184] β-Cell proliferation and insulin secretion are investigated using an organoid model of human pancreatic islets. Mechanisms of action of such effects are evaluated by western blot, RNA-seq and histology of key organs (pancreas, liver, muscle, fat, kidney, and others) and islet organoids. Example 5 – Effects on β-Cell Proliferation

[0185] The effects of ziftomenib on β- and non-β-cell proliferation in human pancreatic islet microtissues (MTs) from two donors (Donor 1: 33 years old, male, BMI 33.15, %HbA1C 5.7, normal islet classification; and Donor 2: 33 years old, female, BMI 28.82, %HbA1C 5.5, normal islet classification) under standard (STD) (5.5 mM glucose) and glucotoxic (GTX) (8 mM glucose) conditions were evaluated (compared with vehicle and harmine as a positive control). Following islet aggregation (day 0 to day 5) and a 4-day hold to day 9, samples were treated as follows: (a) vehicle under STD conditions (21 days); (b) vehicle under GTX conditions (21 days); (c) hold under STD conditions for 17 days and add harmine (10 µM) for 4 days; (d) hold under STD conditions for 4 days and add ziftomenib (100 nM) for 17 days; (e) hold under STD conditions for 4 days and add ziftomenib (500 nM) for 17 days; (f) hold under GTX conditions for 4 days and add ziftomenib (100 nM) for 17 days; and (g) hold under GTX conditions for 4 days and add ziftomenib (500 nM) for 17 days.

[0186] MTs were washed twice with PBS, fixed for 15 min in 4% PFA, washed twice more with PBS, and stored in PBS with 0.05% sodium azide until staining. MTs were then permeabilized with permeabilization buffer (Triton® X-100, 0.5% in PBS w / o Mg2+Ca2+) and washed twice with PBS. Proliferating cells were labeled by 10 μM EdU (marker for proliferating cells) using the Click-it reaction (Click-iT™ EdU Alexa Fluor™ 647 HCS Assay, Thermo Fisher). MTs were then washed twice with PBS and blocked with 10% FCS solution to prevent nonspecific antibody binding before overnight incubation with rabbit mAB NKX6.1WSGR Reference No.47535-754.601 [EPR20405] (Abcam, ab221549) (a pancreatic β-cell-specific transcription factor used as a marker for β-cells) at a 1:200 dilution in antibody dilution buffer (10% FCS, 0.2% Triton® X- 100 in PBS w / o Mg2+Ca2+). Goat anti-rabbit secondary antibody AF568 (ThermoFisher A11036) was used as secondary antibody at a 1:200 dilution in antibody dilution buffer, along with DAPI (nucleus staining marker for counting total cells).

[0187] Samples were evaluated by 3D microscopic analysis for levels of β- and non-β-cell proliferation. MTs were transferred into Akura 384-well plates and cleared with ScaleS4 solution for 3D imaging. Images were acquired using a Yokogawa CQ1 Benchtop High- Content Analysis System, taking fluorescent images in 3 µm z-steps in blue, red, and far-red channels. DAPI-, NKX6.1-, and EdU-positive nuclei and signal colocalization were quantified using a customized CellPathfinder pipeline. Statistical significance was determined with One- way ANOVA and Dunnett’s multiple comparisons test, rejecting the null hypothesis at p = 0.05. Outliers were detected with ROUT’s outlier test (Q=5%). No outlier test was applied to the proliferating cell analysis. DAPI- (total cells), NKX6.1- (pancreatic β-cells), and EdU- (proliferating cells) positive nuclei and signal colocalization were assessed according to the marker status shown in Table 4. Table 4. Cell types Status of staining markers Total β-cells NKX6.1 +, DAPI+ Proliferating β-cells EdU+, NKX6.1+, DAPI+ Proliferating non-β-cells EdU+, NKX6.1-, DAPI+

[0188] In MTs from both donors, culturing of the samples in the GTX medium for 21 days did not lead to any overt changes in MT morphology compared to samples cultured in the STD medium. Ziftomenib treatment (17 days) did not profoundly change the MT morphology of the MTs, but treatment with ziftomenib at 500 nM resulted in a slightly darker colored and smaller MTs. The color change may be a result of accumulation of zinc, a mineral that is required for insulin storage and maturation of insulin granules. The observed changes were not consistent with necrosis or excessive cell death, which is often accompanied by disturbed microtissue morphology at the edges and / or dark spots heterogeneously distributed within the islet microtissue. Harmine treatment mildly disturbed MT edges for MTs from both donors.

[0189] For the Donor 1 samples (FIG.15), GTX conditions alone did not drive β-cell proliferation (FIG.17A) but did induce non-β-cell proliferation (FIG.17B). Harmine treatment significantly stimulated both β-cell and non-β-cell proliferation. Treatment with ziftomenib (100 nM) increased the proliferating β-cell count moderately under STD conditions andWSGR Reference No.47535-754.601 significantly under GTX conditions (average 1 cell / MT / 4 days vs. average 0 cell / MT / 4 days for vehicle, p<0.05) but did not induce non-β-cell proliferation compared to vehicle under either set of conditions. A measurement of 1 cell / MT / 4 days can be extrapolated to estimated production of 19 β-cells in 17 days of treatment or ~600,000 β-cells for 3 months of treatment. (Data shown represent mean + SEM of a single donor with 8 to 16 replicates. Unpaired t-test of GTX DMSO control vs. STD DMSO control (red stars). Unpaired t-test between each condition and its respective solvent control (blue stars): *p < 0.05, **p < 0.01, ***p < 0.001.)

[0190] The quantification results for tested MT samples from Donor 2 are shown in FIG.16. Data represent mean + SEM for the single donor with 8 to 16 replicates. Unpaired t-test between each condition and its respective vehicle control (blue stars): * p<0.05, ** p<0.01, *** p<0.001. Ziftomenib induced a significant increase in β-cell proliferation at both concentrations (FIG.18A), most prominently under GTX conditions with 100 nM ziftomenib (average 9.3 cells / MT / 4 days in 100 nM ziftomenib vs 0.25 cells / MT / 4 days in DMSO, p < 0.0001). This increase exceeded the effect for harmine under STD conditions (6.25 cells / MT / 4 days in harmine) (FIG.18A).

[0191] Non-β-cell proliferation in Donor 2 samples was significantly induced by harmine treatment (199 cells / MT / 4 days in harmine vs 36 cells / MT / 4 days for vehicle, p < 0.0001) (FIG. 18B), while ziftomenib (100 nM) did not enhance the proliferation of non-β-cells (31 cells / MT / 4 days) compared to vehicle.

[0192] The total count of β-cells significantly increased in the 100 nM ziftomenib Donor 2 samples under both sets of conditions, while harmine had no effect (FIG.18C). The increase for the 100 nM ziftomenib / GTX samples was ~120 cells / MT, approximately 80 cells beyond the 40 that would be estimated to arise from an average of 9.3 proliferating β-cells every 4 days. These results indicate that proliferation may have been faster earlier in compound treatment period (as EdU was only included during the final 4 days) or that other mechanisms may have played a role in proliferation.

[0193] Treatment with ziftomenib (500 nM) did not increase proliferating β-cells significantly in Donor 1 samples (FIG.17A) and showed a weak but significant effect on β-cell proliferation under GTX conditions in Donor 2 samples (2.17 cells / MT / 4 days vs 0.25 cells / MT / 4 days in vehicle, p < 0.05) (FIG.18A). This treatment did decrease proliferating non-β-cells in samples from both donors, suggesting potentially adverse effects on MT health at that dose level (FIG. 17A; FIG.18A).

[0194] In sum, these results demonstrate that the menin inhibitor, ziftomenib, is a strong inducer of β-cell proliferation with minimum effect on proliferation of other cell types.WSGR Reference No.47535-754.601

[0195] This experiment was repeated with MT from Donor 3 (44 years old, %HbA1C 6.5, islet classification T2D), dosing with ziftomenib at 33 nM and 100 nM instead of 100 nM and 500 nM. Ziftomenib significantly induced β-cell proliferation under GTX (8mM) conditions in a dose-dependent manner, but not under STD (5.5mM) conditions (FIG.19A). Data are presented as mean + SEM of a single donor with 8 to 16 replicates. One-way ANOVA with Dunnett’s multiple comparisons test within each glucose group, vs. the respective solvent control (black stars) was performed. Unpaired t-test between each condition and its respective solvent control was performed (blue stars): *, p < 0.05; **, p < 0.01; ***p < 0.001.

[0196] The total number of β-cells increased at both doses under both STD (5.5mM) and GTX (8mM) conditions (FIG.19B), indicating potential for β-cell mass expansion in tissues. Data presented as mean + SEM of a single donor with 8 to 16 replicates. One-way ANOVA with Dunnett’s multiple comparisons test within each glucose group, vs. the respective solvent control (black stars) was performed. Unpaired t-test between each condition and its respective solvent control was performed (blue stars): *, p < 0.05; **, p < 0.01; ***, p < 0.001.

[0197] Consistent with the previous experiment, ziftomenib did not induce proliferation of non-β-cells (as measured by proliferating non-β-cell count) at either dose, and total number of non-β-cells did not change (at 33 nM) or slightly decreased (at 100 nM) (as measured to total non-β-cell count) in the Donor 3 model. These results indicate ziftomenib induced proliferation of β-cells specifically at these doses, with potential to promote pancreatic function by expanding β-cell mass and restoring glucose homeostasis. Example 6 – Dose-Response Study of Effects of Ziftomenib in ZDF Rat Model of Advanced Disease

[0198] ZDF male rats (~ 350 g, average FBG 27 mmol / L; Charles River, Beijing, China) were assigned to 4 groups (12 animals in each group) based on body weight and blood glucose (random blood glucose level (not fasted) > 11.1 mM). Baseline average FBG level for this set of animals was significantly higher (~26.9 vs.~23.6; p < 0.001) and baseline average insulin level was lower (approx.13 vs.15 ng / mL) for this cohort than for Example 1, indicating advanced disease and reduced pancreatic function in animals studied in this experiment.

[0199] Animals were fed on a high calorie / high sugar diet (Beijing Keao Xieli Feed Co., Ltd., Cat. No. K5008). Dosing was performed for 42 days as follows: a) vehicle (5 mL / kg, PO, QD); b) ziftomenib (100 mg / kg, PO, QD); c) ziftomenib (50 mg / kg, PO, QD); and d) ziftomenib (25 mg / kg, PO, QD). FBG levels and fasting insulin levels of 12 rats per group were measured on Days 0, 6, 12, 21, 27, 33 and 42. On Day 42, 8 rats per group were sacrificed. In each of theWSGR Reference No.47535-754.601 vehicle, 50 mg / kg, and 100 mg / kg groups, FBG and fasting insulin of the remaining 4 rats per group were measured on Days 48 and 56 during a two-week wash-out period.

[0200] Despite the increased disease burden in the tested animals, ziftomenib significantly reduced FBG at the 50 and 100 mg / kg dose levels at Day 42 (FIG.20A; *, p<0.05; **, p<0.01; ****, p<0.001), including two animals in the 100 mg / kg group that achieved normalized FBG levels at Day 42 (≤7 mM). Fasting insulin levels were elevated after just two weeks of dosing at 50 and 100 mg / kg and were significantly increased by Day 42 relative to vehicle (FIG.20B; *, p<0.05; **, p<0.01; ****, p<0.001). The FBG effects were maintained during the two-week wash-out period in both the 50 and 100 mg / kg treatment groups (FIG.20C; *, p<0.05; **, p<0.01), which, when combined with the other results presented here, suggests that ziftomenib treatment may expand β-cell mass by stimulating β-cell proliferation in pancreas and restoring pancreatic function. Example 7 – Mechanism of Action of Ziftomenib in ZDF Rat Model Example 7.1 – RNASeq Analysis of ZDF Rat Tissues

[0201] To evaluate the mechanism of action of effects of ziftomenib in the ZDF rat studies, liver, gastrocnemius muscle, pancreas, kidney, heart, brown fat, perirenal fat, and epididymal fat are taken from ZDF rats at the end of dosing period (on Day 27 in Example 1 or on Day 42 in Example 6). In a separate dosing experiment, tissue samples are collected at Day 7 or Day 14 of dosing, before insulin levels increased to the point that might affect the insulin sensitivity of the tissues. Liver, perirenal fat, brown fat, and muscle are processed for RNA-seq and analyzed for differentially expressed genes and differentially regulated pathways by ziftomenib treatment comparing to vehicle. In some aspects, alteration of one or glucose metabolism pathways is implicated, e.g., upregulated or downregulated. Example 7.2 – In Vitro Experiments to Assess Effects of Ziftomenib on Glucose Uptake

[0202] C2C12 myoblasts are differentiated into myotubes by low serum media. Myotubes are treated with various doses of ziftomenib (1-1000 nM) or vehicle for up to 6 days. For modeling liver and fat, HepG2 (human hepatocellular carcinoma cell line) and adipocytes differentiated from 3T3-L1 (mouse embryonic fibroblasts) are used. 3T3-L1 cells are cultured in high- confluency for 2 days to induce adipogenesis. Glucose uptake for all materials is evaluated using the Glucose Uptake-GloTMAssay kit (Promega, Catalog J1341) with a luminescence plate reader. In some aspects, cells treated with ziftomenib have increased glucose uptake relative to untreated cells.WSGR Reference No.47535-754.601 Example 8 – Dose-Response Evaluation of Ziftomenib in β-Cell Proliferation and Islet Function in Ex Vivo Human Islet Culture

[0203] Human donor islet cells are treated with ziftomenib at various doses for 6 days under standard (5.5 mM glucose) and glucotoxic (11 mM glucose) conditions. Glucose stimulated insulin secretion (GSIS), basal insulin levels, stimulated insulin levels, chronic insulin levels, and insulin content are measured to assess improvement in islet function of the human donor islet cells. Insulin level measurements are conducted by ELISA and protein assay. Imaging analyses are performed to quantify proliferating β-cells and islet viability using methods analogous to those described herein. Example 9 – In Vivo Diabetes / Obesity Models Example 9.1:

[0204] BKS db / db mice (Charles River, JAX® Mice Strain), which model Phases 1 to 3 of type 2 diabetes and obesity, are dosed with vehicle, semaglutide (10 nmol, QD), ziftomenib (100 mg / kg, QD), and the combination for 28 days. Changes in body weight, fasting blood glucose levels, and insulin levels are monitored weekly. %HbA1C is measured on Day 1 and Day 28. An OGTT is performed on Day 28. Serum cholesterol and triglyceride levels are measured on Day 28. Food and water intake are measured every one to three days. Example 9.2 – DIO (Diet-Induced Obesity) Mouse Model

[0205] Diet-Induced Obese C57BL / 6J mice (The Jackson Laboratory, JAX® Mice Strain B6 DIO, Cat. No.380050) serve as a model for obesity-associated symptoms such as insulin resistance, fatty-liver disease, and elevated cholesterol and triglycerides, and as a mode for prediabetes or early-stage diabetes with mildly elevated blood glucose levels, glucose intolerance, and insulinemia.

[0206] DIO mice are dosed with vehicle, semaglutide (10 nmol, QD), ziftomenib (100 mg / kg, QD), and the combination for 28 days. Changes in body weight, fasting blood glucose levels, and insulin levels are monitored weekly. An OGTT is performed on Day 28. Serum cholesterol and triglyceride levels are measured on Day 28. Food and water intake are measured every one to three days. Liver histology is performed to identify improvements in liver steatosis scores relevant to fatty-liver disease (FLD) or metabolic associated steatohepatitis (MASH). Example 10 – In Vivo Type 1 Diabetes Model

[0207] Diabetes is induced in C57BL / 6J, NOD-scid, and / or NSG male mice (The Jackson Laboratory). Streptozotocin (STZ) is an alkylating agent that targets insulin-producing β-cells inWSGR Reference No.47535-754.601 the pancreas, mimicking Type 1 diabetes phenotypes in mice. Prepared mice are treated with vehicle or ziftomenib (100 mg / kg, QD) and FBG, insulin, c-peptide, and %HbA1C will be monitored. An OGTT is performed at the end of the dosing period. Example 11 – In Vivo Combination Studies

[0208] Combinations of ziftomenib and semaglutide or ziftomenib and metformin are studied in the ZDF rat model (ziftomenib-metformin only), the db / db mouse model, or the DIO mouse model, using methods analogous to those described herein. Combinations of ziftomenib and a thiazolidinedione, with or without metformin, are evaluated using the same models. Combinations of ziftomenib and a sulfonylurea, with or without metformin, are evaluated using the same models. Example 12 – Effect of Ziftomenib on β-Cell Mass in ZDF Rat Pancreatic Islets

[0209] ZDF male rats (~ 350 g, ave. FBG 27 mmol / L; Charles River, Beijing, China) were assigned to 4 groups (12 animals in each group) based on body weight and blood glucose (random blood glucose level (not fasted) > 11.1 mM). Animals were fed on a high calorie / high sugar diet (Beijing Keao Xieli Feed Co., Ltd., Cat. No. K5008). Dosing was performed for 42 days with a) vehicle (5 mL / kg, PO, QD) or b) ziftomenib (100 mg / kg, solution in 20% HP-β- CD, PO, QD). On Day 42, 8 rats per group were sacrificed and pancreatic tails were harvested and prepared as FFPE samples. Sections were cut at a thickness of 4 µm, dried in an oven for 2 hours, and deparaffinized. Three sections were harvested from each tissue, with each section spaced 4 µm apart. Sections were prepared and insulin was detected by immunofluorescence as follows. Antigen retrieval was conducted by immersing sections in EDTA retrieval solution and heating in a microwave at high power for 5 min, then at medium-high power for 15 min, then cooling to room temperature for 30 min, and rinsing with PBS 3 times, 5 min each. Goat serum was added to the sections, which were then blocked at room temperature for 10 min. Primary antibody incubation was conducted by discarding the blocking solution and adding the primary antibody (Recombinant Anti-Insulin antibody, dilution 1:2000, Abcam, CAT ab181547, LOT GR297560-12), incubating at 37°C for 1 h, then rinsing with PBS 3 times, 5 min each. Secondary antibody incubation was conducted by adding an HRP-labeled secondary antibody (panovue, CAT 10015001050, LOT PN031123AD) and incubating at room temperature for 10 min, then rinsing with PBS 3 times, 5 min each. TSA fluorescent dye PPD520 (panovue, dilution 1:1000, CAT 10005100100, LOT PN120722AD) was added and the mixtures were incubated at room temperature for 10 min, then rinsed with PBS 3 times, 5 min each. A second antigen retrieval was conducted by immersing sections in EDTA retrieval solution and heatingWSGR Reference No.47535-754.601 them in a microwave at high power for 5 min, then at medium-high power for 15 min, then cooling to room temperature for 30 min, and rinsing with PBS 3 times, 5 minutes each. The resulting sections were mounted using a DAPI-containing mounting medium. Insulin analysis was conducted using HALO 3.6.4134 software, with islet, insulin-positive, and cell count analyses performed using DenseNet V2 (HALO AI), Area Quantification v2.4.3, and Nucli Seg (HALO AI) (Indica Labs), respectively. Insulin-positive areas (representing pancreatic β-cell mass) were normalized by the total areas analyzed (%) (FIG.21; plot of insulin-positive areas normalized by the total areas analyzed, indicated as %. *, p<0.05; **, p<0.01; ****, p<0.001). Pancreatic samples from Zucker-lean rats were used as a healthy rat control.

[0210] Areas of β-cell mass represented by the insulin-positive areas were significantly decreased in samples from vehicle-treated animals compared to samples from healthy rats (Zucker-lean), consistent with β-cell loss and β-cell mass decline associated with extensive diabetes progression in this model. In contrast, samples from ziftomenib-treated animals showed significantly larger insulin-positive areas than samples from vehicle-treated animals, and approached the results for healthy rats, providing further evidence that ziftomenib regenerates functional β-cell mass and restores insulin production in diabetic animals with failing pancreatic function. Example 13 - Ziftomenib restores molecular function of β cells in pancreatic islet cells

[0211] Pancreatic tail samples of ZDF rats were powdered on liquid N2and immediately dissolved in Trizol. RNA extraction was performed using a Qiagen RNeasy Mini Kit, and RNA integrity was measured using an Agilent 2100 Bioanalyzer with an Agilent RNA 6000 Nano Kit. Libraries were constructed using RiboRNA Plus seq-NOVA-9G Kit and total RNA-seq was performed (pair-end 150) on a NovaSeq 6000 platform.

[0212] Adapters were trimmed and short reads (<75 bp) were removed. The clean reads were mapped to the rat reference genome (rat6) using STAR. RSEM (V1.3.3) was used to quantify the transcript abundance. The TMM (trimmed mean of m-values) method was used to normalize the expression levels among samples using edgeR software. The differential expression analysis was performed using edgeR and the enrichment analyses of GO and KEGG were performed.

[0213] The NGS analysis showed that the cell cycle inhibitor gene cyclin-dependent kinase inhibitor 1A (cdkn1a, p21) was significantly downregulated in ziftomenib-treated group compared to vehicle (Table 5). These results were consistent with previous reports that indicated that inhibition of menin by ziftomenib stimulates β-cell proliferation by downregulating the cell cycle inhibitor genes (Karnik et al., Proc. Natl. Acad. Sci. USA 2005,WSGR Reference No.47535-754.601 102(41), 14659-14664; Milne et al., Proc. Natl. Acad. Sci. USA 2005, 102(3), 749-754). Mature β-cell marker genes (Mafa and Nkx6.1) and the glucose transporter gene (Slc2a2) were significantly upregulated, suggesting that the produced β-cells became mature and functional. Furthermore, insulin genes (Ins1 and Ins2) were significantly upregulated, confirming that proliferating β cells were able to produce insulin. Table 5. Gene Expression Changes (Log2 Fold Change) β-Cell Genes Log2 Fold Change Padj-value Ins1 1.59 0.0011 Ins2 1.45 0.0010 Mafa 1.86 0.0053 Nkx6-1 1.30 0.0025 Slc2a2 1.35 5.73E-05 Cdkn1a -1.42 4.00E-07 Example 14 – Sequencing of human islet microtissue samples and ZDF rat pancreatic samples for ER stress markers

[0214] Pancreatic β-cells are under constant stress particularly in diabetic conditions where blood glucose levels are consistently high. Producing insulin peptides creates a considerable burden and drives cells into ER stress. The persistent ER stress in diabetic conditions is thought to lead to β-cell malfunction and death. Thus inhibiting / easing ER stress is considered as among the effective methods to prevent β-cells from apoptosis in diabetes.

[0215] To evaluate the effects of ziftomenib on ER stress in the diabetes setting, microtissue samples from a 44-year-old T2D male patient donor (HbA1C, 6.5%; diabetic) were used for NGS analysis using a TempO-seq (Templated Oligo-Sequencing) method. Following islet aggregation (day 0 to day 5) and a 4-day hold to day 9, samples were treated as follows: (a) vehicle under STD conditions (21 days) (STD solvent); (b) vehicle under GTX conditions (21 days) (GTX solvent); (c) hold under STD conditions for 17 days and add harmine (10 µM) for 4 days; (d) hold under STD conditions for 4 days and add ziftomenib (100 nM) for 17 days (STD Zifto); and (e) hold under GTX conditions for 4 days and add ziftomenib (100 nM) for 17 days (GTX Zifto).

[0216] As shown in Table 6, the samples showed upregulation of ER-stress / unfolded protein response (UPR) pathways under high-glucose conditions compared to normal glucose conditions, as high glucose directly induces ER-stress or induces significant insulin production, which results in a burden for ER. In ziftomenib-treated samples, ER stress pathways were downregulated under high glucose conditions, almost restoring the ‘normal’ situation without cellular stress, indicating that ziftomenib may protect β-cells and promote their survival by easing cellular stress.WSGR Reference No.47535-754.601 Table 6. Kyoto Encyclopedia of Genes and Genomes (KEGG) Pathway Analysis Results. Metabolic Pathway Normalized Enrichment Score GTX solvent / STD Zifto / GTX Zifto / GTX Zifto / STD solvent STD solvent GTX solvent STD Zifto Hallmark Unfolded Protein Response 2.21 No change -1.68 No change Reactome Antigen Processing Ubiquitination No change No change -1.56 No change Proteasome Degradation Reactome Unfolded Protein Response 2.14 No change No change No change UPR WP Proteasome Degradation No change -1.89 -2.01 No change

[0217] NGS analysis of ZDF rat pancreatic samples from Example 13 also showed downregulation of ER-stress related genes (Hsp1al and Txnip) and apoptosis genes (Casp12 and Casp9) in samples treated with ziftomenib (Table 7) compared to samples treated with vehicle, supporting the observation in human islet microtissues and suggesting that ziftomenib inhibits ER-stress, protects β-cells from cell death, and promotes β-cell survival under diabetic / high glucose conditions. Table 7. Gene expression changes indicated as log2 fold change Stress-Related Genes Log2 Fold Change Padj-value Hspa4l -2.03 5.97E-24 Txnip -2.14 4.26E-19 Casp12 -1.07 0.008513 Casp9 -1.03 0.000738 Example 15 – Effect of Menin Inhibitors on Lean Muscle Mass

[0218] The body compositions of ZDF rats were measured using Echo-MRI (Bruker minispec LF90 II) after 27 days of dosing with: a) vehicle (5 mL / kg, PO, QD); b) ziftomenib (100 mg / kg, solution in 20% HP-β-CD, PO, QD); or c) revumenib (75 mg / kg, PO, BID). Both ziftomenib and revumenib significantly increased the body lean mass (representative of muscle content) (FIG.22A) and decreased the body fat mass (FIG.22B) in ZDF rats. These results suggest that both menin inhibitors can induce muscle gain. Fat mass represents body fat; lean mass represents mostly muscle. T-test was performed; *, p<0.05; **, p<0.01.

[0219] In an analogous experiment, the body compositions of db / db mice were measured using Echo-MRI (Bruker minispec LF90 II) after 26 days of dosing with: a) vehicle (5 mL / kg, PO, QD); b) ziftomenib (100 mg / kg, solution in 20% HP-β-CD, PO, QD); or c) revumenib (50WSGR Reference No.47535-754.601 mg / kg, PO, BID). Ziftomenib and revumenib significantly increased the body lean mass while they did not affect the body fat mass in db / db mice (FIG.23A / 23B; Plots of body composition measurements of db / db mice. Fat mass represents body fat, lean mass represents mostly muscle. *, p<0.05; **, p<0.01; ****, p<0.001). Thess results support the observation in ZDF rats and promote the idea that menin inhibitors as a class can expand the muscle mass. Example 16 - Ziftomenib upregulates PPAR pathway in ZDF rat muscles

[0220] ZDF rats (6 animals per group) were treated for 28 days with 100 mg / kg ziftomenib or vehicle. Gastrocnemius muscle samples were then harvested and preserved in RNA-later. RNA extraction was performed using a Qiagen RNeasy Mini Kit, and RNA integrity was measured using an Agilent 2100 Bioanalyzer with an Agilent RNA 6000 Nano Kit. Libraries were constructed using a Vazyme Stranded mRNA (polyA plus) Library KIT and polyA+ RNA-seq was performed (pair-end 150) on a NovaSeq 6000 platform. Adapters were trimmed and short reads (<75 bp) were removed. The clean reads were mapped to the rat reference genome (rat6) using STAR. RSEM ((V1.3.3) (Li , et al., BMC Bioinform.2011, 12, 323)) was used to quantify the transcript abundance. TMM (trimmed mean of m-values) method was used to normalize the expression levels among samples using edgeR software. Differential expression analysis was performed using edgeR and enrichment analyses were performed. KEGG pathway enrichment analysis showed that the PPAR pathway was upregulated (padj value 2.15E-06, rich factor 0.10, gene number 7) in ZDF rat gastrocnemius muscle in the ziftomenib-treated group compared to vehicle group.

[0221] While some embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. It is not intended that the invention be limited by the specific examples provided within the specification. While the invention has been described with reference to the aforementioned specification, the descriptions and illustrations of the embodiments herein are not meant to be construed in a limiting sense. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. Furthermore, it shall be understood that all aspects of the invention are not limited to the specific depictions, configurations, or relative proportions set forth herein which depend upon a variety of conditions and variables. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is therefore contemplated that the invention shall also cover any such alternatives, modifications, variations, or equivalents. It is intended that the following claims define the scope of the invention and thatWSGR Reference No.47535-754.601 methods and structures within the scope of these claims and their equivalents be covered thereby.

Claims

WSGR Reference No.47535-754.601 CLAIMS Listing of Claims 1. A method of improving glycemic control in an individual comprising administering to the individual a menin inhibitor.

2. A method of reducing %HbA1c in an individual with elevated %HbA1c comprising administering to the individual a menin inhibitor.

3. The method of claim 2, wherein the administering reduces %HbA1c in the individual by at least 0.5pp, at least 0.6pp, at least 0.7pp, at least 0.8pp, at least 0.9pp, at least 1pp, at least 1.1pp, at least 1.2pp, at least 1.3pp, at least 1.4pp, at least 1.5pp, at least 1.6pp, at least 1.7pp, at least 1.8pp, at least 1.9pp, or at least 2.0pp, or from 0.5 to 2.0pp, or from 0.8 to 1.8pp, or from 1.0 to 1.8pp, or about 0.5pp, 0.6pp, 0.7pp, 0.8pp, 0.9pp, 1.0pp, 1.1pp, 1.2pp, 1.3pp, 1.4pp, 1.5pp, 1.6pp, 1.7pp, 1.8pp, 1.9pp, or 2.0pp, or to a %HbA1c of less than 7.0%, less than 6.5%, less than 6.4%, less than 6.3%, less than 6.2%, less than 6.1%, less than 6.0%, less than 5.9%, less than 5.8%, or less than 5.7%, or to a %HbA1c of about 5.7 to 6.4%, or to a %HbA1c of 5.7% or less.

4. The method of claim 2 or claim 3, wherein the administering reduces the %HbA1c within 12 months, 9 months, 6 months, 5 months, 4 months, 3 months, 2 months, 1 month, 56 weeks, 52 weeks, 48 weeks, 40 weeks, 32 weeks, 28 weeks, 24 weeks, 20 weeks, 16 weeks, 12 weeks, 8 weeks, 6 weeks, 5 weeks, 4 weeks, 3 weeks, 2 weeks, or 1 week.

5. The method of any one of claims 2 to 4, wherein the administering reduces the %HbA1c by at least 0.8pp, at least 0.9pp, at least 1pp, at least 1.1pp, at least 1.2pp, at least 1.3pp, at least 1.4pp, at least 1.5pp, at least 1.6pp, from 0.8 to 1.8pp, or from 1.0 to 1.8pp, or to a %HbA1c of about 5.7 to 6.4%, or to a %HbA1c of 5.7% or less, within 12 months, 9 months, 6 months, 5 months, 4 months, 3 months, 2 months, 1 month, 6 weeks, 5 weeks, or 4 weeks.

6. A method of reducing body weight in an individual comprising administering to the individual a menin inhibitor.

7. The method of claim 6, wherein the administering reduces body weight in the individual without significant toxicity or significant reduction in appetite or food intake.

8. The method of claim 6 or claim 7, wherein the administering reduces the body weight in the individual within 4 weeks, 6 weeks, 8 weeks, 10 weeks, or 12 weeks, optionally by at least 5%, or at least 10%, or at least 15%, or at least 20%, or by about 5 to 10%, or by about 10 to 20%.

9. A method of reducing fasting blood glucose concentration in an individual comprising administering to the individual a menin inhibitor.WSGR Reference No.47535-754.601 10. The method of claim 9, wherein the administering reduces the fasting blood glucose concentration in the individual by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, or at least 75%.

11. The method of claim 9 or claim 10, wherein the administering reduces the fasting blood glucose concentration in the individual to below 10 mmol / L, or below 9 mmol / L, or below 8 mmol / L, or below 7.5 mmol / L, or below 7.0 mmol / L, or below 6.5 mmol / L, or below 6.0 mmol / L, or below 5.6 mmol / L, or below 5.5 mmol / L, or below 5.0 mmol / L, or to about 6.5 to 7.5 mmol / L, or to about 7.0 to 7.5 mmol / L, or to about 5.0 to 8.0 mmol / L, or to about 3.9 mmol / L to 6.9 mmol / L, or to about 3.9 mmol / L to 5.6 mmol / L; or below 150 mg / dL, or below 126 mg / dL, or to a level of 100 to 125 mg / dL, or to a level of 70 to 100 mg / dL; or by at least 10 mg / dL, at least 15 mg / dL, at least 20 mg / dL, at least 25 mg / dL, or at least 30 mg / dL, or at least 35 mg / dL, or at least 40 mg / dL, or at least 45 mg / dL, or at least 50 mg / dL.

12. The method of any one of claims 9 to 11, wherein the administering reduces the fasting blood glucose concentration in the individual within 60 weeks, 56 weeks, 52 weeks, 48 weeks, 40 weeks, 36 weeks, 30 weeks, 24 weeks, 12 weeks, 10 weeks, 8 weeks, 7 weeks, 6 weeks, 5 weeks, 4 weeks, 3 weeks, 2 weeks, or 1 week.

13. The method of any one of claims 9 to 12, wherein the administering reduces the fasting blood glucose concentration for at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, or at least 12 months.

14. A method of improving postprandial glucose control in an individual comprising administering to the individual a menin inhibitor.

15. The method of claim 14, wherein the administering limits the individual’s 2-hour postprandial glucose concentration during an oral glucose tolerance test to less than 200 mg / dL, or less than 190 mg / dL, or less than 180 mg / dL, or less than 170 mg / dL, or less than 160 mg / dL, or less than 150 mg / dL, or less than 140 mg / dL, or to 130 to 200 mg / dL; or to an amount that is at least 25, at least 50, at least 60, or at least 70 mg / dL less than placebo.

16. A method of improving insulin sensitivity in an individual comprising administering to the individual a menin inhibitor.

17. The method of claim 16, wherein the administering reduces a HOMA-IR for the individual to less than 2.9, less than 2.8, less than 2.7, less than 2.6, less than 2.5, less than 2.4, less than 2.3, less than 2.2, less than 2.1, less than 2.0, less than 1.9, less than 1.8, less than 1.7, less than 1.6, less than 1.5, less than 1.4, less than 1.3, less than 1.2, less than 1.1, or less thanWSGR Reference No.47535-754.601 18. The method of claim 16 or claim 17, wherein the administering reduces a HOMA-IR within 4 weeks, 3 weeks, 2 weeks, or 1 week.

19. The method of any one of claims 16 to 18, wherein the administering reduces the HOMA-IR without significant toxicity or significant reduction in appetite or food intake.

20. A method of improving pancreatic β-cell function in an individual comprising administering to the individual a menin inhibitor.

21. The method of claim 20, wherein the administering increases a HOMA-B for the individual by at least 1.1 times, at least 1.2 times, at least 1.3 times, 1.4 times, at least 1.5 times, at least 2 times, at least 2.5 times, or at least 3 times over the HOMA-B value for the individual prior to administering the menin inhibitor.

22. The method of claim 20 or claim 21, wherein the administering increases a HOMA-B within 4 weeks, 3 weeks, 2 weeks, or 1 week.

23. The method of any one of claims 20 to 22, wherein the administering increases a HOMA-B without significant toxicity or significant reduction in appetite or food intake.

24. A method of increasing fasting plasma insulin concentration in an individual comprising administering to the individual a menin inhibitor.

25. The method of claim 24, wherein the administering increases the fasting plasma insulin concentration in the individual by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, or at least 10%.

26. The method of claim 24 or claim 25, wherein the administering increases the fasting plasma insulin concentration in the individual within 6 months, within 5 months, within 4 months, within 3 months, within 2 months, or within 1 month.

27. The method of any one of claims 24 to 26, wherein the administering does not induce hypoglycemia in the individual.

28. The method of any one of claims 24 to 27, wherein the administering increases the concentration of c-peptide in the individual.

29. The method of claim 28, wherein the administering increases the c-peptide concentration in the individual within 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 2 months, 3 months, or 6 months.

30. The method of claim 28 or claim 29, wherein the administering increases the c-peptide concentration in the individual to about 0.5 to 2.0 ng / mL, or about 0.9 to 1.8 ng / mL, or to at least 0.5 ng / mL, or at least 0.8 ng / mL, or by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%.

31. A method of increasing proliferation of islet β-cells in an individual comprising administering to the individual a menin inhibitor.WSGR Reference No.47535-754.601 32. The method of claim 31, wherein the administering does not significantly increase proliferation of other cells.

33. The method of claim 31 or 32, wherein the administering selectively increases proliferation of islet β-cells.

34. The method of any one of claims 31 to 33, wherein the administering increases proliferation of islet β-cells by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, or 100%.

35. The method of any of the preceding claims, comprising administering to the individual a combination agent, optionally wherein the combination agent comprises a glucagon-like peptide-1 (GLP-1) receptor agonist (e.g., tirzepatide, lixisenatide, exenatide, semaglutide, albiglutide, dulaglutide, or liraglutide), an antihyperglycemic agent, insulin (e.g., administered by syringe, insulin pen, or insulin pump; e.g., pre-mixed, rapid-acting, ultra rapid-acting, inhaled, short-acting, intermediate-acting, or ultra long-acting, or a combination) or an insulin derivative, an insulin secretagogue, an SGLT2 inhibitor (e.g., dapagliflozin, canagliflozin, empagliflozin, or ertugliflozin), a meglitinide (e.g., repaglinide or nateglinide), a dipeptidyl peptidase IV (DPP-4) inhibitor (e.g., sitagliptin, saxagliptin, alogliptin, or linagliptin), a sulfonylurea (e.g., glimerpiride, glyburide, chlorpropamide, glipizide, tolbutamide, or tolazamide), a biguanide (e.g., metformin), a PPAR agonist (e.g., a PPAR-gamma agonist) such as a thiazolidinedione (e.g., pioglitazone or rosiglitazone), a thiazolidinedione (e.g., pioglitazone or rosiglitazone), a bile acid sequestrant (e.g., colesevelam), an alpha-glucosidase inhibitor (e.g., miglitol or acarbose), a dopamine receptor agonist (e.g., bromocriptine), an activin type II receptor blocker (e.g., monoclonal antibody, bimagrumab), or an amylin mimetic (e.g., pramlintide acetate, cagrilintide), or a combination thereof (e.g., metformin and pioglitazone, rosiglitazone, glyburide, canagliflozin, sitagliptin, linagliptin, alogliptin, saxagliptin, glipizide, repaglinide, or dapagliflozin; glimerpiride and rosiglitazone or pioglitazone; empagliflozin and linagliptin; alogliptin and pioglitazone), or a combination thereof, or a β-cell replacement therapy.

36. The method of any one of claims 1 to 35, wherein the administering of the menin inhibitor is an adjunct to diet and / or exercise.

37. The method of any one of claims 1 to 36, wherein individual is pre-diabetic.

38. The method of any one of claims 1 to 37, wherein the individual has been diagnosed with diabetes, optionally wherein the diabetes is type 1 diabetes, type 2 diabetes, or gestational diabetes.

39. The method of any one of claims 1 to 38, wherein the individual exhibits prominent insulin resistance and / or defective pancreatic insulin secretion.WSGR Reference No.47535-754.601 40. The method of any one of claims 1 to 38, wherein the administering does not produce any one or more of a significant toxicity or a significant risk of neutropenia, thrombocytopenia, QTc prolongation, adverse cardiovascular event, differentiation syndrome, or tumor lysis syndrome.

41. The method of any one of claims 1 to 40, wherein the administering: (a) reduces a risk of one or more adverse cardiac events in the individual, optionally wherein the one or more adverse events are selected from developing cardiovascular disease, worsening cardiovascular disease, major adverse cardiovascular event in an individual with cardiovascular disease, death from cardiovascular causes, myocardial infarction (optionally wherein the myocardial infarction is a non-fatal myocardial infarction), stroke (optionally wherein the stroke is a non-fatal stroke); or (b) provides cardiac protection to the individual.

42. The method of any one of claims 1 to 41, wherein the administering of the menin inhibitor: (a) increases lean muscle mass; (b) reduces muscle atrophy from co-administration of a GLP-1R agonist; (c) improves insulin sensitivity; or (d) upregulates the PPAR pathway in the individual.

43. The method of any one of claims 1 to 42, comprising administering the menin inhibitor daily, intermittently, every other day, daily every other week, once per day, twice per day, or three times per day.

44. The method of any one of claims 1 to 43, wherein the menin inhibitor is ziftomenib, SNDX-5613 (revumenib), VTP-50469, JNJ-75276617, DS-1594, DS-1594a, DS-1594b, DSP- 5336, MI-3454, M-808, A300-105A, BN104, Compound A, Compound B1, Compound B2, or Compound C, or a pharmaceutically acceptable form thereof.

45. The method of any one of claims 1 to 44, wherein the menin inhibitor is a compound of Formula (I-A), (I-B), (II-A), (III-A), (IV-A), or (IV-B), or a pharmaceutically acceptable form thereof.

46. The method of any one of claims 1 to 45, wherein the menin inhibitor is ziftomenib or a pharmaceutically acceptable form thereof.

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