Discovery of Novel Benzothiazepinones as Irreversible Covalent Glycogen Synthase Kinase 3β Inhibitors for the Treatment of Acute Promyelocytic Leukemia

Recently,
irreversible inhibitors have attracted great interest
in antitumors due to their advantages of forming covalent bonds to
target proteins. Herein, some benzothiazepinone compounds (BTZs) have
been designed and synthesized as novel covalent GSK-3β inhibitors
with high selectivity for the kinase panel. The irreversible covalent
binding mode was identified by kinetics and mass spectrometry, and
the main labeled residue was confirmed to be the unique Cys14 that
exists only in GSK-3β. The candidate 4-3 (IC50 = 6.6 μM) showed good proliferation inhibition
and apoptosis-inducing ability to leukemia cell lines, low cytotoxicity
on normal cell lines, and no hERG inhibition, which hinted the potential
efficacy and safety. Furthermore, 4-3 exhibited
decent pharmacokinetic properties in vivo and remarkably
inhibited tumor growth in the acute promyelocytic leukemia (APL) mouse
model. All the results suggest that these newly irreversible BTZ compounds
might be useful in the treatment of cancer such as APL.