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Design of the First‐in‐Class,Highly Potent Irreversible Inhibitor Targeting the Menin‐MLL Protein–Protein Interaction |
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| Authors: | Dr Shilin Xu Dr Angelo Aguilar Dr Tianfeng Xu Dr Ke Zheng Dr Liyue Huang Prof?Dr Jeanne Stuckey Dr Krishnapriya Chinnaswamy Dr Denzil Bernard Dr Ester Fernández‐Salas Dr Liu Liu Dr Mi Wang Donna McEachern Sally Przybranowski Caroline Foster Prof?Dr Shaomeng Wang |
| Affiliation: | 1. Comprehensive Cancer and Departments of Internal Medicine, Pharmacology and Medicinal Chemistry, University of Michigan, Ann Arbor, MI, USA;2. Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA;3. Department of Pathology, University of Michigan, Ann Arbor, MI, USA |
| Abstract: | 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. |
| Keywords: | drug design irreversible inhibitors menin-MLL protein– protein interaction MLL leukemia |
