Design of Potent Menin–KMT2A Interaction Inhibitors with Improved <i>In Vitro</i> ADME Properties and Reduced hERG Affinity
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<sub>50</sub> as low as 13 nM, and selected compounds demonstrated improved <i>in vitro</i> ADME properties, de-risked CYP3A4 dependency, and lower hERG inhibition.
Authors
- S.M. Bester (ORCID: https://orcid.org/0000-0001-7137-0090)
- Jennifer Fulton
- Ellen R. Laird (ORCID: https://orcid.org/0009-0001-1902-9941)
- J. Kimbrough
- Anurag Singh (ORCID: https://orcid.org/0000-0003-4705-8683)
- Bruno D. Chapsal
- Bismarck Campos (ORCID: https://orcid.org/0000-0001-5667-386X)
- Joshua R. Dahlke
- Joseph McCown
- Adam W. Cook (ORCID: https://orcid.org/0009-0003-0172-1424)
- Karin Brown
- Keith A. Strand (ORCID: https://orcid.org/0000-0001-8885-0162)
- Mark J. Chicarelli
- Lance Wollenberg (ORCID: https://orcid.org/0009-0002-4791-8655)
- Yeyun Zhou
- Melissa C. Holt (ORCID: https://orcid.org/0000-0002-7883-924X)
- Jay B. Fell (ORCID: https://orcid.org/0000-0002-5770-1225)
- Shelley Allen (ORCID: https://orcid.org/0000-0001-7870-740X)
- Jim Wong (ORCID: https://orcid.org/0000-0001-9597-5537)
- Anna L. Guarnieri
- Tung‐Chung Mou (ORCID: https://orcid.org/0000-0001-6554-1519)
- D Kahn (ORCID: https://orcid.org/0009-0003-3506-6341)
- Donald S. Backos (ORCID: https://orcid.org/0000-0001-6735-6210)
- Jacob M. O’Leary
- Cole L. Cruz
- Alex Bergstrom
- John J. Gaudino (ORCID: https://orcid.org/0009-0004-7043-2770)
- Patrick M. Barbour
- Macedonio J. Mejia
- Brad Newhouse
- Tanna Bettendorf
- John P. Fischer (ORCID: https://orcid.org/0000-0002-3373-1016)
- David A. Moreno
- Matthew G. McDonald (ORCID: https://orcid.org/0000-0003-4667-9728)
- Amy L. Crooks
- Rebecca Linwood
- Rebecca Abrahamsen
- Andrew C. Allen
- Martha E. Rodriguez
- Erik P. Hansen
- Matthew Martinson
- Paul D. Larsen
- Mark L. Boys
- Alida Eide
- Matthew Gargus
- Lenka Sinik
- Eric E. Touney
Institutions
- Pfizer (United States) (US)
- Pfizer (France) (FR)
Publication Details
- Journal
- ACS Medicinal Chemistry Letters
- Published
- 2024-12-31
- DOI
- https://doi.org/10.1021/acsmedchemlett.4c00311
- Citations
- 3
- Primary Topic
- Acute Myeloid Leukemia Research
- Type
- article
- Field-Weighted Citation Impact
- 1.36