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.
Xu, S., Aguilar, A., Huang, L., Xu, T., Zheng, K., Mceachern, D., … Wang, S. (2020). Discovery of m-808 as a highly potent, covalent, small-molecule inhibitor of the menin-mll interaction with strong in vivo antitumor activity. Journal of Medicinal Chemistry, 63(9), 4997–5010. https://doi.org/10.1021/acs.jmedchem.0c00547