Targeting Tumor Heterogeneity: The Design and Efficacy of TGN-1076, a CDK7 Inhibitor

The objective of this research was to address the genetic heterogeneity found in tumors, which can cause transcriptional dysregulation and reliance on specific gene expression regulators. Super-enhancers, which are linked to transcriptional coactivators and chromatin marks, have been observed in tumor cells at genes known to drive cancer. These super-enhancers are often reliant on cyclin-dependent kinase 7 (CDK7) for initiating transcription. High levels of CDK7 are associated with poor outcomes in various cancers. The study aimed to develop a therapeutic targeting CDK7's catalytic ATP pocket, leading to the creation of TGN-1076, an improved analog of the previously discovered inhibitor TGN-1062.

Utilizing structure-guided and medicinal chemistry, the researchers optimized TGN-1062 to enhance potency, selectivity, and drug-like properties. In vitro kinase assays and cell viability tests were conducted, along with Western Blotting to assess RNA Pol II phosphorylation and MYC protein levels.

TGN-1076 was found to inhibit CDK7 with high potency and selectivity. It effectively halted the growth of various cancer cells, with pancreatic cancer cells showing the greatest sensitivity. The compound significantly reduced the phosphorylation of RNA Pol II and the expression of MYC and its downstream target MCL-1 in treated pancreatic cancer cells. TGN-1076 also demonstrated high activity against hERG and various P450 isozymes.

The study concludes with the development of a novel CDK7 inhibitor, with ongoing efforts to optimize the compound for further studies on absorption, distribution, metabolism, excretion, toxicity, and tumor efficacy. The research was presented at the Annual Meeting of the American Association for Cancer Research in 2020.