Discovery of ZLC491 as a Potent, Selective, and Orally Bioavailable CDK12/13 PROTAC Degrader

Selective degradation
of cyclin-dependent kinases 12 and 13 (CDK12/13)
emerges as a new potential therapeutic approach for triple-negative
breast cancer (TNBC) and other human cancers. While several proteolysis-targeting
chimera (PROTAC) degraders of CDK12/13 were reported, none are orally
bioavailable. Here, we report the discovery of ZLC491 as a potent, selective, and orally bioavailable CDK12/13 PROTAC
degrader. The compound effectively degraded CDK12 and CDK13 with DC50 values of 32 and 28 nM, respectively, in TNBC MDA-MB-231
cells. Global proteomic assessment and mechanistic studies revealed
that ZLC491 selectively induced CDK12/13 degradation
in a cereblon- and proteasome-dependent manner. Furthermore, the molecule
efficiently suppressed transcription and expression of long genes,
predominantly a subset of genes associated with DNA damage response,
and significantly inhibited proliferation of multiple TNBC cell lines.
Importantly, ZLC491 achieved an oral bioavailability
of 46.8% in rats and demonstrated potent in vivo degradative
effects on CDK12/13 in an MDA-MB-231 xenografted mouse model.