Design of the First-in-Class, Highly Potent Irreversible Inhibitor Targeting the Menin-MLL Protein-Protein Interaction
Angew. Chem. Int. Ed., 2018
DOI: 10.1002/anie.201711828
Shaomeng Wang, Shilin Xu, Angelo Aguilar, Tianfeng Xu, Ke Zheng, Liyue Huang, Jeanne Stuckey, Krishnapriya Chinnaswamy, Denzil Bernard, Ester Fernández-Salas, Liu Liu, Mi Wang, Donna McEachern, Sally Przybranowski, Caroline Foster
We report the structure-based design of M-525 as the first-in-class, highly potent, irreversible small-molecule inhibitor of the menin-MLL interaction. M-525 targets cellular menin protein at sub-nanomolar concentrations and achieves low nanomolar potencies in cell growth inhibition and in suppression of MLL-regulated gene expression in MLL leukemia cells. M-525 demonstrates high cellular specificity over non-MLL leukemia cells and is >30-times more potent than its corresponding reversible inhibitors. Mass spectroscopic analysis and co-crystal structure of M-525 in complex with menin firmly establish its mode of action. A single administration of M-525 effectively suppresses MLL-regulated gene expression in tumor tissue. An efficient procedure was developed to synthesize M-525. Our study demonstrates that irreversible inhibition of menin may represent a promising therapeutic strategy for MLL leukemia.
