Lessons Learned from Past Cyclin-Dependent Kinase Drug Discovery Efforts

摘要

Inhibition of cyclin-dependent kinases (CDKs) hasbecome an effective therapeutic strategy for treating various diseases,especially cancer. Over almost three decades, although great effortshave been made to discover CDK inhibitors, many of which haveentered clinical trials, only four CDK inhibitors have been approved.In the process of CDK inhibitor development, many difficulties andmisunderstandings have hampered their discovery and clinicalapplications, which mainly include inadequate understanding of thebiological functions of CDKs, less attention paid to pan- and multi-CDK inhibitors, nonideal isoform selectivity of developed selectiveCDK inhibitors, overlooking themetabolic stability of earlydiscovered CDK inhibitors, no effective resistance solutions, and a lack of available combination therapy and effective biomarkersfor CDK therapies. After reviewing the mechanisms of CDKs and the research progress of CDK inhibitors, this perspectivesummarizes and discusses these difficulties or lessons, hoping to facilitate the successful discovery of more useful CDK inhibitors

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