2. Academic Validation
  3. Design of the First-in-Class, Highly Potent Irreversible Inhibitor Targeting the Menin-MLL Protein-Protein Interaction

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

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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