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

Aguilar, Angelo; Zheng, Ke; Xu, Tianfeng; Xu, Shilin; Huang, Liyue; Fernandez-Salas, Ester; Liu, Liu; Bernard, Denzil; Harvey, Kaitlin P.; Foster, Caroline; McEachern, Donna; Stuckey, Jeanne; Chinnaswamy, Krishnapriya; Delproposto, James; Kampf, Jeff W.; Wang, Shaomeng

doi:10.1021/acs.jmedchem.9b00021

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

Journal Article · Sat Jun 22 00:00:00 EDT 2019 · Journal of Medicinal Chemistry

DOI:https://doi.org/10.1021/acs.jmedchem.9b00021· OSTI ID:1544865

Aguilar, Angelo ^[1]; Zheng, Ke ^[2]; Xu, Tianfeng ^[1]; Xu, Shilin ^[1]; Huang, Liyue ^[1]; Fernandez-Salas, Ester ^[1]; Liu, Liu ^[1]; Bernard, Denzil ^[1]; Harvey, Kaitlin P. ^[1]; Foster, Caroline ^[1]; McEachern, Donna ^[1]; Stuckey, Jeanne ^[1]; Chinnaswamy, Krishnapriya ^[1]; Delproposto, James ^[1]; Kampf, Jeff W. ^[1]; ^[1]

Univ. of Michigan, Ann Arbor, MI (United States)
Univ. of Michigan, Ann Arbor, MI (United States); Sichuan Univ., Chengdu (China)

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 K_d 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. Overall, we conclude that further optimization of M-89 may lead to a new class of therapy for the treatment of MLL leukemia.

View Accepted Manuscript (DOE)

Research Organization:: Advanced Photon Source (APS), Argonne National Laboratory (ANL), Argonne, IL (US)

Sponsoring Organization:: Michigan Economic Development Corporation; National Institutes of Health (NIH); USDOE

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 1544865

Journal Information:: Journal of Medicinal Chemistry, Journal Name: Journal of Medicinal Chemistry Journal Issue: 13 Vol. 62; ISSN 0022-2623

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: ENGLISH

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