Discovery and research progress of CDK8 inhibitors.

The 53 kDa serine/threonine protein kinase known as cyclin-dependent kinase 8 (CDK8) controls transcription by attaching itself to mediator complexes or phosphorylating transcription factors. As a crucial protein with dual oncogenic and physiological regulatory roles, CDK8 is frequently overexpressed in colorectal cancer (CRC), breast cancer, melanoma, and other tissues, making it a potential antitumor target. Furthermore, it plays important roles in inflammatory responses, fibrotic processes, and the control of bone metabolism, making it a promising therapeutic target for a variety of disease areas. In recent years, the discovery of CDK8 inhibitors has expanded, and many new, highly selective inhibitors have been proposed as possible treatments for human illnesses. This review outlines the most recent developments in CDK8 inhibitors, focusing on their structural classification, structure-activity connections, binding modalities, kinase selectivity, and cross-disease pharmacological activities. It also addresses development obstacles and optimization techniques for achieving selective CDK8 inhibition, aiming to offer recommendations for the rational design and clinical application of CDK8/19-targeting agents.