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

  • Angew Chem Int Ed Engl. 2018 Feb 5;57(6):1601-1605. doi: 10.1002/anie.201711828.
Shilin Xu  1 ,  Angelo Aguilar  1 ,  Tianfeng Xu  1 ,  Ke Zheng  1 ,  Liyue Huang  1 ,  Jeanne Stuckey  2 ,  Krishnapriya Chinnaswamy  2 ,  Denzil Bernard  1 ,  Ester Fernández-Salas  3 ,  Liu Liu  1 ,  Mi Wang  1 ,  Donna McEachern  1 ,  Sally Przybranowski  1 ,  Caroline Foster  1 ,  Shaomeng Wang  1
Affiliations
  • 1. Comprehensive Cancer and Departments of Internal Medicine, Pharmacology and Medicinal Chemistry, University of Michigan, 1600 Huron Parkway, Ann Arbor, MI, 48109, USA.
  • 2. Life Sciences Institute, University of Michigan, 210 Washtenaw, Ann Arbor, MI, 48109, USA.
  • 3. Department of Pathology, University of Michigan, 1600 Huron Parkway, Ann Arbor, MI, 48109, USA.
PMID: 29284071 DOI: 10.1002/anie.201711828
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
MLL leukemia; drug design; irreversible inhibitors; menin-MLL protein-protein interaction.
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