Design of the First‐in‐Class, Highly Potent Irreversible Inhibitor Targeting the Menin‐MLL Protein–Protein Interaction
[1]
- Comprehensive Cancer and Departments of Internal Medicine Pharmacology and Medicinal Chemistry University of Michigan 1600 Huron Parkway Ann Arbor MI 48109 USA
- Life Sciences Institute University of Michigan 210 Washtenaw Ann Arbor MI 48109 USA
- Department of Pathology University of Michigan 1600 Huron Parkway Ann Arbor MI 48109 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.
- Sponsoring Organization:
- USDOE
- Grant/Contract Number:
- AC02-06CH11357
- OSTI ID:
- 1416993
- Journal Information:
- Angewandte Chemie, Journal Name: Angewandte Chemie Vol. 130 Journal Issue: 6; ISSN 0044-8249
- Publisher:
- Wiley Blackwell (John Wiley & Sons)Copyright Statement
- Country of Publication:
- Germany
- Language:
- English
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