Design of the First-in-Class, Highly Potent Irreversible Inhibitor Targeting the Menin-MLL Protein–Protein Interaction

The structure-based design of M-525 as the first-in-class, highly potent, irreversible small-molecule inhibitor of the menin-MLL interaction is presented. M-525 targets cellular menin protein at sub-nanomolar concentrations and achieves low nanomolar potencies in cell growth inhibition and in the su...

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Published in:Angewandte Chemie (International ed.) 2017-12, Vol.57 (6)
Main Authors: Xu, Shilin, Aguilar, Angelo, Xu, Tianfeng, Zheng, Ke, Huang, Liyue, Stuckey, Jeanne, Chinnaswamy, Krishnapriya, Bernard, Denzil, Fernández‐Salas, Ester, Liu, Liu, Wang, Mi, McEachern, Donna, Przybranowski, Sally, Foster, Caroline, Wang, Shaomeng
Format: Article
Language:English
Subjects:
INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
irreversible inhibitors
menin-MLL
MLL leukemia
protein-protein interaction
rug design
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Summary:The structure-based design of M-525 as the first-in-class, highly potent, irreversible small-molecule inhibitor of the menin-MLL interaction is presented. M-525 targets cellular menin protein at sub-nanomolar concentrations and achieves low nanomolar potencies in cell growth inhibition and in the suppression of MLL-regulated gene expression in MLL leukemia cells. M-525 demonstrates high cellular specificity over non-MLL leukemia cells and is more than 30 times more potent than its corresponding reversible inhibitors. Mass spectrometric 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. This study demonstrates that irreversible inhibition of menin may be a promising therapeutic strategy for MLL leukemia.
ISSN:1433-7851
1521-3773