Structure-Based Discovery of M-89 as a Highly Potent Inhibitor of the Menin-Mixed Lineage Leukemia (Menin-MLL) Protein–Protein Interaction
Year: 2019
Type: article
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 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 IC 50 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.
Source: Journal of Medicinal Chemistry
Institutions: University of Michigan, U-M Rogel Cancer Center
Language: English
Subfield: Drug Discovery
Domain: Life Sciences
Open Access status: green
Awards: G102163711, G107546177, G1313983767, G1664757510, G1947107004, G2287611682, G262962599, G3075337988, G3152346458, G3329398301, G416541740, G4773269573, Targeting the menin-MLL1 complex for new therapeutics, G498139845, G5607048534, G5906309288, G6848031779, G6918803902, G7147508703, University of Michigan Rogel Cancer Center Support Grant 2023-2028, G969889393, G993149817
OpenAlex ID: W2951484711