Covalent inhibitors of menin-MLL interaction for diabetes mellitus
Inventors
Butler, Thomas • Palmer, James T.
Assignees
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Publication Number
US-12251385-B2
Publication Date
2025-03-18
Expiration Date
Abstract
Disclosed herein are heterocyclic compounds that inhibit the binding of menin and MLL or MLL fusion proteins for the treatment of diabetes mellitus. Also described are specific covalent inhibitors of menin-MLL interaction. Also disclosed are pharmaceutical compositions that include the described compounds. Methods of using the menin-MLL covalent inhibitors are disclosed, alone or in combination with other therapeutic agents, for the treatment of diabetes mellitus.
Core Innovation
The invention relates to a method for reducing HbA1c in a patient in need thereof by administering a therapeutically effective amount of a compound according to Formula (I) or a pharmaceutically acceptable salt thereof. The compounds are defined by specific structural features within Formula (I), including A as carbon or nitrogen and defined relationships among Cy, Q, Z, X, Y, and W, together with substituent options for Cy2, R4a, R4b, R5a, R6a, R6b, R6c, m, and n. The disclosure includes compounds according to multiple structural formulas and pharmaceutically acceptable salts.
The claimed substituent framework includes nitrogen-containing ring systems via Cy2 and supports amide/carboxamide-like motifs and sulfonyl/sulfone-like motifs through the defined choices for W and the −X−W−Y− segment. The disclosure further includes alternative chemotypes presented as compounds according to multiple structural formulas, with variable R7 heterocycle options and variability in R6a/R6b/R6c substituents.
The disclosure further indicates that covalent inhibitors of the menin–MLL (and MLL fusion) interaction form covalent bonds with menin cysteine residues, including Cys329, and inhibit menin–MLL activity in vivo by binding to the MLL site on menin. It associates this inhibition with treatment of diabetes mellitus, including type 1 diabetes, type 2 diabetes, gestational diabetes, MODY, steroid induced diabetes, and double diabetes.
The disclosure also describes reduction of HbA1c and presents in vivo efficacy figure summaries using glucose, insulin, C-peptide, HbA1c, OGTT, and HOMA-IR in ZDF and STZ models.
Claims Coverage
The consolidated claims coverage identifies one independent claim directed to reducing HbA1c in a patient in need thereof by administering a therapeutically effective amount of a Formula (I) compound or pharmaceutically acceptable salt. Across the combined items, the claims define one principal inventive feature set, with dependent claims refining the compound selection and adding quantitative HbA1c reduction timing and magnitude constraints.
HbA1c reduction by administering Formula (I) compound or salt
A method for reducing HbA1c in a patient in need thereof by administering a therapeutically effective amount of a compound according to Formula (I) or a pharmaceutically acceptable salt thereof, where A is carbon or nitrogen and the structural definitions for Cy, Q, Z, X, Y, and W include the specified options for Cy2, R4a, R4b, R5a, R6a, R6b, R6c, m, and n.
Specific linkage region patterns within the Formula (I) scaffold
The method of claim 1 further specifying that the −X−W−Y region is one of the enumerated linkage sub-patterns, including amide/sulfonamide-type group patterns as provided.
Use of specified formula families as the administered compound
The method of claim 1 wherein the compound is defined by one of Formula (VIIa), (VIIb), (VIIc), (VIIIa), (VIIIb), (VIIIc), (XXVIa), (XXVIb), or (XXVIc), including a pharmaceutically acceptable salt thereof.
Use of Formula (XVI) or Formula (XVII) as the administered compound
The method of claim 1 wherein the compound is a compound of Formula (XVI) or Formula (XVII), including a pharmaceutically acceptable salt thereof.
HbA1c reduction threshold within one month
The method of claim 1 wherein HbA1c is lowered by at least 0.5% within one month of dosing.
HbA1c reduction range tied to days 21 to 29
The method of claim 1 wherein HbA1c is lowered by 1% to 3.5% between day 21 and day 29 of dosing.
Overall, the consolidated claim coverage centers on reducing HbA1c in a patient by administering a therapeutically effective amount of a Formula (I) compound or pharmaceutically acceptable salt, while dependent claims refine the compound identity through specific formula families and linkage patterns and add quantified HbA1c reduction timing and magnitude constraints.
Stated Advantages
Reduces HbA1c in a patient in need thereof.
Lowers HbA1c by at least 0.5% within one month of dosing.
Lowers HbA1c by 1% to 3.5% between day 21 and day 29 of dosing.
Improved potency (IC50) and menin active-site occupancy are stated for the disclosed menin-MLL inhibitors.
Documented Applications
Treatment of diabetes mellitus by inhibiting menin–MLL activity in vivo using covalent inhibitors of the menin–MLL (and MLL fusion) interaction.
Treatment of type 1 diabetes, type 2 diabetes, gestational diabetes, maturity onset diabetes of the young, steroid diabetes, and double diabetes.
Use in a method for reducing HbA1c in a patient in need thereof.
Nonclinical menin-MLL inhibitory activity evaluation, including IC50 determination in MOLM13 and HL60 cells.
Restoring or maintaining glycemic control in type 2 diabetes mellitus rat models using Compound 10, including reductions in glucose, insulin, C-peptide, HOMA-IR, and HbA1c.
Diabetic rat efficacy studies in Zucker Diabetic Fatty (ZDF) rats and Streptozotocin (STZ)-induced rats, including durability after short dosing and after post-treatment washout.
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