Discovery and characterization of SY-1365, a selective, covalent inhibitor of CDK7

Recent studies suggest that targeting transcriptional machinery can lead to potent and selective anti-cancer effects in cancers dependent on high and constant expression of certain transcription factors for growth and survival. CDK7 is the catalytic subunit of the CDK-activating kinase (CAK) complex. Its function is required for both cell cycle regulation and transcriptional control of gene expression. CDK7 has recently emerged as an attractive cancer target since its inhibition leads to decreased transcript levels of oncogenic transcription factors, especially those associated with super-enhancers (SE). Here we describe a selective CDK7 inhibitor SY-1365, which is currently in clinical trials in populations of ovarian and breast cancer patients (NCT03134638). In vitro, SY-1365 inhibited cell growth of many different cancer types at nanomolar concentrations. SY-1365 treatment decreased MCL1 protein levels, and cancer cells with low BCL-XL expression were found to be more sensitive to SY-1365. Transcriptional changes in acute myeloid leukemia (AML) cell lines were distinct from those following treatment with other transcriptional inhibitors. SY-1365 demonstrated substantial anti-tumor effects in multiple AML xenograft models as a single agent; SY-1365-induced growth inhibition was enhanced in combination with the BCL2 inhibitor venetoclax. Anti-tumor activity was also observed in xenograft models of ovarian cancer, suggesting the potential for exploring SY-1365 in the clinic in both hematological and solid tumors. Our findings support targeting CDK7 as a new approach for treating transcriptionally addicted cancers.