Covalent CDK-7 inhibitors as new anti-cancer agents

ABSTRACT All cancers are characterized by altered transcriptional programs, and misregulated transcription factors are amongst the most potent oncogenes known, yet this class of oncogenes has been difficult to drug directly. A different approach to attack misregulated oncogenic transcription is to develop small molecules against gene control components that are critical in the expression of these oncogenic transcription factors. We describe here the discovery and development of a class of potent covalent inhibitors of CDK7, a kinase that plays important roles in both transcription and the cell cycle. This class of CDK7 inhibitors shows low nM potency in biochemical and cellular assays and we show that these compounds work primarily by inhibiting transcription and inducing apoptosis in sensitive cell lines. Interestingly, we find CDK7 to be associated with a class of recently described transcriptional regulatory elements termed ‘super-enhancers’, and show that these compounds specifically antagonize super-enhancer driven gene expression to selectively revert oncogenic transcriptional programs in multiple disease models. These compounds are well tolerated in mice and we have developed an assay to show target engagement in vivo. Testing these compounds in multiple mouse models of human cancer (CDX, PDX and GEMM) we see in vivo efficacy in T-ALL, neuroblastoma and SCLC (including regressions). We describe specific examples of the impact of CDK7 inhibition on the oncogenic transcription program in these models.