Novel Selective Inhibitors of Cyclin Dependent Kinase 7

Cyclin-dependent kinase (CDK) family members that trigger passage through the cell cycle have been considered as attractive therapeutic targets for years, especially for cancer. Over time this enthusiasm vanished, since the 1st generation of CDK inhibitors resulted in disappointing clinical outcomes due to small therapeutic windows. CDK inhibitors affecting processes such as transcription and RNA processing have caught less attention so far, although experimental evidence for their involvement in different pathological processes is emerging. As a general regulator of cell cycle and transcription, CDK7 is being discussed as a therapeutic target for cancer although it has also been considered a double edged sword because of its central role in transcription (TFIIH component) as well as in the cell cycle (CDK-activating kinase (CAK)). Extending the role of the molecular target, CDK7, to a CDK7 inhibitor, the double edged sword hypothesis argues either in favor of good oncology target properties or safety issues. To achieve clarity for this conundrum, we generated picomolar and mono-selective CDK7 inhibitors through rationale design efforts. Inhibitors from our proprietary lead series demonstrated in vivo efficacy in a breast cancer xenograft model without causing toxic or adverse effects. Even more surprisingly, such highly selective CDK7 inhibitors showed a distinct responder profile of sensitive cell lines from a panel of more than 120 different human cancer cell lines. Therefore, selective CDK7 inhibitors shall not be considered as non-specific cytotoxic agents. Rather they are novel starting points of personalized therapy for certain tumor types.