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Journal of Medicinal Chemistry

Journal of Medicinal Chemistry

IF: 6.8
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Structure-Based Discovery of M-89 as a Highly Potent Inhibitor of the Menin-Mixed Lineage Leukemia (Menin-MLL) Protein–Protein Interaction

Published:22 June 2019 DOI: 10.1021/acs.jmedchem.9b00021 PMID: 31244110
Angelo Aguilar, Ke Zheng, Tianfeng Xu, Shilin Xu, Liyue Huang, Ester Fernandez-Salas, Liu Liu, Denzil Bernard, Kaitlin P. Harvey, Caroline Foster, Donna McEachern, Jeanne Stuckey, Krishnapriya Chinnaswamy, James Delproposto, Jeff W. Kampf, Shaomeng Wang*

Abstract

Inhibition of the menin-mixed lineage leukemia (MLL) protein–protein interaction is a promising new therapeutic strategy for the treatment of acute leukemia carrying MLL fusion (MLL leukemia). We describe herein our structure-based design, synthesis, and evaluation of a new class of small-molecule inhibitors of the menin-MLL interaction (hereafter called menin inhibitors). Our efforts have resulted in the discovery of highly potent menin inhibitors, as exemplified by compound 42 (M-89). M-89 binds to menin with a Kd value of 1.4 nM and effectively engages cellular menin protein at low nanomolar concentrations. M-89 inhibits cell growth in the MV4;11 and MOLM-13 leukemia cell lines carrying MLL fusion with IC50 values of 25 and 55 nM, respectively, and demonstrates >100-fold selectivity over the HL-60 leukemia cell line lacking MLL fusion. The determination of a co-crystal structure of M-89 in a complex with menin provides the structural basis for their high-affinity interaction. Further optimization of M-89 may lead to a new class of therapy for the treatment of MLL leukemia.

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