Discovery of M‑1121 as an Orally Active Covalent Inhibitor of Menin-MLL Interaction Capable of Achieving Complete and Long-Lasting Tumor Regression

Targeting
the menin-MLL protein–protein interaction is being
pursued as a new therapeutic strategy for the treatment of acute leukemia
carrying MLL-rearrangements (MLLr leukemia). Herein, we report M-1121,
a covalent and orally active inhibitor of the menin-MLL interaction
capable of achieving complete and persistent tumor regression. M-1121
establishes covalent interactions with Cysteine 329 located in the
MLL binding pocket of menin and potently inhibits growth of acute
leukemia cell lines carrying MLL translocations with no activity in
cell lines with wild-type MLL. Consistent with the mechanism of action,
M-1121 drives dose-dependent down-regulation of HOXA9 and MEIS1 gene expression in the MLL-rearranged
MV4;11 leukemia cell line. M-1121 is orally bioavailable and shows
potent antitumor activity in vivo with tumor regressions
observed at tolerated doses in the MV4;11 subcutaneous and disseminated
models of MLL-rearranged leukemia. Together, our findings support
development of an orally active covalent menin inhibitor as a new
therapy for MLLr leukemia.