Efficient Pancreatic Cancer Treatment: Targeting CDK7 with a Novel Oral Inhibitor

The purpose of this study was to develop a small molecule inhibitor targeting CDK7, a protein that plays a crucial role in the transcription process and is linked to poor outcomes in several types of cancer. Super-enhancers, which are key regulatory regions, are heavily reliant on CDK7 for their function. The researchers utilized a fragment library screening method based on the crystal structure of human CDK7 and an optimization process to identify the lead inhibitor, TGN-1062. This compound was evaluated through in vitro kinase assays, cell viability tests, and Western Blotting to measure the effects on RNA Pol II phosphorylation and c-Myc protein levels.

The results highlighted the discovery of TGN-1062, a reversible CDK7 inhibitor with high selectivity and an IC50 of 33 nM. It showed a significant sensitivity in pancreatic cancer cell lines with a GI50 of less than 0.4 μM and effectively reduced the phosphorylation of RNA Pol II and c-Myc expression in MiaPaca2 cells. TGN-1062 also exhibited good oral bioavailability in mouse models. Further refinement led to TGN-1069, which maintained potency against CDK7 and demonstrated even greater selectivity over CDK2 and CDK5.

In conclusion, the researchers successfully developed a novel, selective, and orally bioavailable CDK7 inhibitor, with TGN-1069 emerging as a promising preclinical candidate. This compound is currently being evaluated for its effects on kinome profiling, super-enhancer binding protein activities, ADME-Tox properties, and efficacy in pancreatic cancer models. The study was presented at the American Association for Cancer Research Annual Meeting in 2019.