Discovery of M-808 as a Highly Potent, Covalent, Small-Molecule Inhibitor of the Menin-MLL Interaction with Strong <i>In Vivo</i> Antitumor Activity.
Basic Information
ID: ALA4342524
Journal: J Med Chem
Title: Discovery of M-808 as a Highly Potent, Covalent, Small-Molecule Inhibitor of the Menin-MLL Interaction with Strong In Vivo Antitumor Activity.
Authors: Xu S, Aguilar A, Huang L, Xu T, Zheng K, McEachern D, Przybranowski S, Foster C, Zawacki K, Liu Z, Chinnaswamy K, Stuckey J, Wang S.
Abstract: Targeting the menin-MLL protein-protein interaction is a new therapeutic strategy for the treatment of acute leukemia carrying MLL fusion (MLL leukemia). We describe herein the structure-based optimization of a class of covalent menin inhibitors, which led to the discovery of M-808 (16) as a highly potent and efficacious covalent menin inhibitor. M-808 effectively inhibits leukemia cell growth at low nanomolar concentrations and is capable of achieving partial tumor regression in an MV4;11 xenograft tumor model in mice at a well-tolerated dose schedule. Determination of the co-crystal structure of M-808 in complex with menin provides a structural basis for their high-affinity, covalent interactions. M-808 represents a promising, covalent menin inhibitor for further optimization and evaluation toward developing a new therapy for the treatment of MLL leukemia.
CiteXplore: 32338903
DOI: 10.1021/acs.jmedchem.0c00547
Patent ID: ┄