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

Shilin Xu; Angelo Aguilar; Tianfeng Xu; Ke Zheng; Liyue Huang; Jeanne Stuckey; Krishnapriya Chinnaswamy; Denzil Bernard; Ester Fernández-Salas; Liu Liu; Mi Wang; Donna McEachern; Sally Przybranowski; Caroline Foster; Shaomeng Wang

doi:10.1002/anie.201711828

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. Epub 2018 Jan 15.

Authors

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Binding Sites
Cell Line, Tumor
Cell Proliferation / drug effects
Crystallography, X-Ray
Drug Design
Histone-Lysine N-Methyltransferase / antagonists & inhibitors*
Histone-Lysine N-Methyltransferase / metabolism
Humans
Molecular Dynamics Simulation
Myeloid-Lymphoid Leukemia Protein / antagonists & inhibitors*
Myeloid-Lymphoid Leukemia Protein / metabolism
Protein Interaction Domains and Motifs / drug effects
Protein Structure, Tertiary
Proto-Oncogene Proteins / antagonists & inhibitors*
Proto-Oncogene Proteins / metabolism
Small Molecule Libraries / chemistry
Small Molecule Libraries / metabolism
Small Molecule Libraries / pharmacology
Structure-Activity Relationship

Substances

Antineoplastic Agents
KMT2A protein, human
MEN1 protein, human
Proto-Oncogene Proteins
Small Molecule Libraries
Myeloid-Lymphoid Leukemia Protein
Histone-Lysine N-Methyltransferase