Design of Potent Menin-KMT2A Interaction Inhibitors with Improved In Vitro ADME Properties and Reduced hERG Affinity.

IF 3.5 3区医学 Q2 CHEMISTRY, MEDICINAL

ACS Medicinal Chemistry Letters Pub Date : 2024-12-31 eCollection Date: 2025-02-13 DOI:10.1021/acsmedchemlett.4c00311

Bruno D Chapsal, Jennifer R Kimbrough, Stephanie M Bester, Alex Bergstrom, Donald S Backos, Bismarck Campos, Matthew G McDonald, Rebecca Abrahamsen, Andrew C Allen, Patrick M Doerner Barbour, Tanna Bettendorf, Mark L Boys, Karin Brown, Mark J Chicarelli, Adam W Cook, Amy L Crooks, Cole L Cruz, Joshua R Dahlke, Alida Eide, Jay B Fell, Jennifer L Fulton, Matthew Gargus, John J Gaudino, Anna L Guarnieri, Erik P Hansen, Melissa C Holt, Dean R Kahn, Ellen R Laird, Paul D Larsen, Rebecca Linwood, Matthew C Martinson, Joseph McCown, Macedonio J Mejia, David A Moreno, Tung-Chung Mou, Brad Newhouse, Jacob M O'Leary, Martha E Rodriguez, Anurag Singh, Lenka Sinik, Keith A Strand, Eric E Touney, Lance A Wollenberg, Jim Wong, Yeyun Zhou, John P Fischer, Shelley Allen

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Abstract

Inhibitors of the interaction of menin (MEN1) with lysine methyltransferase 2A (KMT2A) have emerged as novel therapeutic options in the treatment of genetically defined acute leukemias. Herein, we describe the structure-based design, synthesis, and biological evaluation of novel inhibitors of the menin-KMT2A interaction. Our structure-activity relationship campaign focused on achieving high antiproliferative cellular activity while mitigating risks associated with CYP3A4-dependent metabolism and hERG inhibition, which were characterized in some early clinical candidates. Our efforts resulted in the discovery of a triazine-based compound series that inhibited MV4-11 leukemia cell line proliferation with IC₅₀ as low as 13 nM, and selected compounds demonstrated improved in vitro ADME properties, de-risked CYP3A4 dependency, and lower hERG inhibition.

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来源期刊

ACS Medicinal Chemistry Letters CHEMISTRY, MEDICINAL-

CiteScore

7.30

自引率

2.40%

发文量

328

审稿时长

1 months

期刊介绍： ACS Medicinal Chemistry Letters is interested in receiving manuscripts that discuss various aspects of medicinal chemistry. The journal will publish studies that pertain to a broad range of subject matter, including compound design and optimization, biological evaluation, drug delivery, imaging agents, and pharmacology of both small and large bioactive molecules. Specific areas include but are not limited to: Identification, synthesis, and optimization of lead biologically active molecules and drugs (small molecules and biologics) Biological characterization of new molecular entities in the context of drug discovery Computational, cheminformatics, and structural studies for the identification or SAR analysis of bioactive molecules, ligands and their targets, etc. Novel and improved methodologies, including radiation biochemistry, with broad application to medicinal chemistry Discovery technologies for biologically active molecules from both synthetic and natural (plant and other) sources Pharmacokinetic/pharmacodynamic studies that address mechanisms underlying drug disposition and response Pharmacogenetic and pharmacogenomic studies used to enhance drug design and the translation of medicinal chemistry into the clinic Mechanistic drug metabolism and regulation of metabolic enzyme gene expression Chemistry patents relevant to the medicinal chemistry field.