Treating Aggressive MYC-Driven Cancers through CDK7 Inhibition
The Sharma Lab’s applied drug discovery research team identifies druggable targets to develop novel cancer treatments. The process begins with in silico structural modeling screens and biological assays to identify novel candidate small molecules. The top hits are further optimized and tested in both in vitro and in vivo models. This study explores CDK7 as a novel therapeutic target.
Deregulated expression of the MYC oncogene is a driving factor for many aggressive cancer types due to the MYC protein’s role in global transcription. Rather than targeting MYC directly, inhibiting CDK7, an upstream regulator of its transcription, has been shown to suppress MYC activity and lead to tumor regression. Previously developed CDK7 inhibitors are disadvantageous due to their non-reversibility and low efficacy. We developed a novel reversible inhibitor of CDK7, designated “TGN-1044”, and tested its effect as a cancer therapeutic in vitro through enzymatic and cell-based assays.
Our in vitro enzymatic activity assay results showed that TGN-1044 is a potent inhibitor of CDK7, with an IC50 of 78 nM. Cell viability assays in different pancreatic cancer lines with varying MYC expression showed TGN-1044’s ability to kill pancreatic cancer cells with IC50’s ranging from 61 to 508 nM. TGN-1044 satisfies many of the requirements our lab seeks from an ideal CDK7 inhibitor. The continued development of this CDK7 inhibitor will further our lab’s goal to treat cancers with high MYC expression.