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

  • J Med Chem. 2019 Jul 11;62(13):6015-6034. doi: 10.1021/acs.jmedchem.9b00021.
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
PMID: 31244110 DOI: 10.1021/acs.jmedchem.9b00021
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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