Cyclin-dependent Kinase 8 (CDK8), a member of the CDKs family, has been widely
focused owing to investigations of its critical roles in transcription and oncogenesis in recent years.
Selective inhibition of CDK8 and its paralog CDK19 offers a novel therapeutic strategy for the
treatment of some cancers. Up to now, though many small molecules against CDK8 have been discovered,
most of them are discontinued in the preclinical trials due to the low selectivity and poor
physicochemical properties. This review mainly summarizes the design strategies of selective CDK8
inhibitors having different chemical scaffolds with the aim to improve the inhibitory activity, selectivity,
metabolic stability and solubility. Their corresponding Structure-activity Relationships (SAR)
are also reviewed. On the basis of the discussion in this review, we hope more effective, selective
and drug-like CDK8 inhibitors will be developed and demonstrate therapeutic values in the near
Keywords: CDK8, CDK19, Selective inhibitors, Design, Structure-activity relationship, Metabolic stability.
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