Abstract
CDK12 and CDK13 are Ser/Thr protein kinases that regulate transcription and co-transcriptional processes. Genetic silencing of CDK12 is associated with genomic instability in a variety of cancers, including difficult-to-treat breast, ovarian, colorectal, brain and pancreatic cancers, and is synthetic lethal with PARP, MYC or EWS/FLI inhibition. CDK13 is amplified in hepatocellular carcinoma. Consequently, selective CDK12/13 inhibitors constitute powerful research tools as well as promising anti-cancer therapeutics, either alone or in combination therapy. Herein the authors discuss the role of CDK12 and CDK13 in normal and cancer cells, describe their utility as a biomarker and therapeutic target, review the medicinal chemistry optimization of existing CDK12/13 inhibitors and outline strategies for the rational design of CDK12/13 selective inhibitors.
Papers of special note have been highlighted as: • of interest; •• of considerable interest
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