Design of Potent Menin–KMT2A Interaction Inhibitors with Improved In Vitro ADME Properties and Reduced hERG Affinity
Year: 2024
Type: article
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 IC 50 as low as 13 nM, and selected compounds demonstrated improved in vitro ADME properties, de-risked CYP3A4 dependency, and lower hERG inhibition.
Source: ACS Medicinal Chemistry Letters
Authors: 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
Institution: Pfizer (United States)
Language: English
Subfield: Organic Chemistry
Field: Chemistry
Domain: Physical Sciences
Open Access status: green
OpenAlex ID: W4405925274