Cyclin-dependent kinase 9 (CDK9) promotes transcriptional elongation through RNAPII pause release. It is also essential for maintaining gene silencing at heterochromatic loci. We recently discovered that CDK9 inhibition reactivates epigenetically silenced genes in cancer, leading to restoration of tumor suppressor gene expression, cell differentiation, and activation of endogenous retrovirus genes. CDK9 inhibition dephosphorylates the SWI/SNF protein BRG1, which contributes to gene reactivation. In addition, CDK9 inhibition sensitizes to the immune checkpoint inhibitor α-PD-1 in vivo, making it an excellent target for epigenetic therapy of cancer. As part of our on-going effort to identify potential novel cancer therapeutics, we have identified a novel series of CDK9 inhibitors. Select members of our novel compound class have broad anti-cancer activity in vitro and are effective in in vivo cancer models.
Moulder Center for Drug Discovery Research
Temple University School of Pharmacy
3307 N Broad Street
Philadelphia, PA 19140