Transcription-regulating kinase CDK8 and its isoform CDK19 play a key role in transcriptional reprogramming, potentiating the effects of some transcription factors that play key roles in cancers, such as SMADs, STATs and NFkB. CDK8/19 have been broadly implicated in cancer metastasis and drug resistance and found to be essential for tumor growth in some cancer types. First-generation CDK8/19 inhibitors have entered clinical trials but there is a need for more active, selective and metabolically stable inhibitors. Here we present our efforts in design, synthesis, structure-activity and optimization of novel quinoline-based compounds as promising CDK8/19 inhibitors. Based on our original CDK8/19 inhibitor Senexin B, structure-based drug design (SBDD) and computational modeling were employed to accelerate inhibitor design and optimization. The newly designed compounds were analyzed through induced-fit docking study, synthesized in-house and evaluated for their CDK8/19 inhibition activity via Lanthascreen and NFkB reporter cell-based assay. The lead optimized compounds then underwent PK analysis and kinome profiling (DiscoverX) to evaluate their metabolic stability and CDK8/19 selectivity. Among the notable leads, one designated Senexin C, showed both a high selectivity for CDK8/19 and significant inhibition potency. Moreover, Senexin C was enriched in tumor tissues relative to blood and exhibits good metabolic stability. Based on SAR information obtained, further studies to improve the potency and PK profiles of quinoline-based lead candidates are in progress.

Design, synthesis, and optimization of quinoline-based CDK8/19 inhibitors as potential anti-cancer agents

ACS Spring Meeting 2021

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.