Discovery of Highly Potent and Selective EZH2 Covalent Inhibitors via Incorporating Basic Amines

Targeted covalent inhibition is a promising strategy
to address
the high dose and acquired drug resistance issues of the first-generation
EZH2 noncovalent inhibitors. Recently we have reported a new generation
of highly potent EZH2 covalent inhibitors, but further optimization
to enhance aqueous solubility is required. Here, we described the
systematic optimization of EPZ-6438 by preserving the
aqueous groups, resulting in the identification of a highly potent
and selective EZH2 covalent inhibitor 13, which displayed
nanomolar potency in biochemical and cellular assays. Moreover, SAM
competition experiments preliminarily confirmed that 13 was noncompetitive with SAM, leading to the remarkable reduction
of the H3K27Me3 marker. In addition, 13 exhibited superior
cell growth inhibition in the EZH2 mutant cancer cell lines. The discovery
of 13 holds promise for the development of highly potent
EZH2 covalent inhibitors.