Discovery of Potent and Selective CDK9 Degraders for Targeting Transcription Regulation in Triple-Negative Breast Cancer

Triple-negative
breast cancer (TNBC) is highly aggressive with
very limited treatment options due to the lack of efficient targeted
therapies and thus still remains clinically challenging. Targeting
transcription-associated cyclin-dependent kinases to remodel transcriptional
regulation shows great promise in cancer therapy. Herein, we report
the synthesis, optimization, and evaluation of new series of heterobifunctional
molecules as highly selective and efficacious CDK9 degraders, enabling
potent inhibition of TNBC cell growth and rapidly targeted degradation
of CDK9. Moreover, the most potent CDK9 degrader (compound 45) induces cell apoptosis in vitro and inhibits tumor
growth in the MDA-MB-231 TNBC model. Furthermore, the RNA-seq, immunohistochemistry
assays demonstrate that the CDK9 degrader downregulates the downstream
targets, such as MYC, at the transcriptional level,
resulting apoptosis in TNBC cells. Our work establishes that 45 is a highly potent and efficacious CDK9 degrader for targeting
transcription regulation, which represents an effective strategy and
great potential as a new targeted therapy for TNBC.