Discovery of a Novel and Potent Cyclin-Dependent Kinase 8/19 (CDK8/19) Inhibitor for the Treatment of Cancer

The mediator kinases CDK8 and CDK19
control the dynamic transcription
of selected genes in response to various signals and have been shown
to be hijacked to sustain hyperproliferation by various solid and
liquid tumors. CDK8/19 is emerging as a promising anticancer therapeutic
target. Here, we report the discovery of compound 12,
a novel small molecule CDK8/19 inhibitor. This molecule demonstrated
not only decent enzymatic and cellular activities but also remarkable
selectivity in CDK and kinome panels. Besides, compound 12 also displayed favorable ADME profiles including low CYP1A2 inhibition,
acceptable clearance, and high oral bioavailability in multiple preclinical
species. Robust in vivo PD and efficacy studies in mice models further
demonstrated its potential use as mono- and combination therapy for
the treatment of cancers.