Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 63, Issue 9, Pages 4997-5010Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.0c00547
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Funding
- National Institutes of Health/National Cancer Institute [R01 CA208267]
- Prostate Cancer Foundation
- Rogel Cancer Center Core Grant from the National Cancer Institutes, NIH [P30 CA046592]
- U.S. DOE [DE-AC02-06CH11357]
- Michigan Technology Tri-Corridor [085P1000817]
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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.
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