9C94

Crystal structure of menin in complex with inhibitor compound 20

This is a non-PDB format compatible entry.

Summary for 9C94

• Entry DOI: 10.2210/pdb9c94/pdb
• Related: 9C92 9C93
• Descriptor: Menin, {5-fluoro-2-[(5-{7-[(1-methylcyclopropyl)methyl]-2,7-diazaspiro[3.5]nonan-2-yl}-1,2,4-triazin-6-yl)oxy]phenyl}[(1R,5S)-3-oxa-8-azabicyclo[3.2.1]octan-8-yl]methanone (3 entities in total)
• Functional Keywords: protein binding, protein binding-inhibitor complex, protein binding/inhibitor
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 115066.22

Authors

Bester, S.M.,Wu, W.-I.,Mou, T.-C. (deposition date: 2024-06-13, release date: 2025-01-15, Last modification date: 2025-03-05)

Primary citation

Chapsal, B.D.,Kimbrough, J.R.,Bester, S.M.,Bergstrom, A.,Backos, D.S.,Campos, B.,McDonald, M.G.,Abrahamsen, R.,Allen, A.C.,Doerner Barbour, P.M.,Bettendorf, T.,Boys, M.L.,Brown, K.,Chicarelli, M.J.,Cook, A.W.,Crooks, A.L.,Cruz, C.L.,Dahlke, J.R.,Eide, A.,Fell, J.B.,Fulton, J.L.,Gargus, M.,Gaudino, J.J.,Guarnieri, A.L.,Hansen, E.P.,Holt, M.C.,Kahn, D.R.,Laird, E.R.,Larsen, P.D.,Linwood, R.,Martinson, M.C.,McCown, J.,Mejia, M.J.,Moreno, D.A.,Mou, T.C.,Newhouse, B.,O'Leary, J.M.,Rodriguez, M.E.,Singh, A.,Sinik, L.,Strand, K.A.,Touney, E.E.,Wollenberg, L.A.,Wong, J.,Zhou, Y.,Fischer, J.P.,Allen, S.
Design of Potent Menin-KMT2A Interaction Inhibitors with Improved In Vitro ADME Properties and Reduced hERG Affinity.
Acs Med.Chem.Lett., 16:224-233, 2025

PubMed 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 as low as 13 nM, and selected compounds demonstrated improved ADME properties, de-risked CYP3A4 dependency, and lower hERG inhibition.

PubMed: 39967615
DOI: 10.1021/acsmedchemlett.4c00311

Experimental method

X-RAY DIFFRACTION (1.98 Å)