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

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.