CDK8 as a therapeutic target for cancers and recent developments in discovery of CDK8 inhibitors

Area of Science:

• Molecular Biology
• Oncology
• Drug Discovery

Background:

• Cyclin-dependent kinases 8 (CDK8) regulates transcription by interacting with the mediator complex and phosphorylating transcription factors.
• CDK8 overexpression is linked to various cancers, notably mediating aberrant Wnt/β-catenin signaling activation, particularly in colorectal cancer (CRC).
• CDK8's oncogenic role positions it as a therapeutic target, although its function is context-dependent.

Purpose of the Study:

• To review the co-crystal structures, biological mechanisms, and dysregulation of CDK8 in cancers.
• To summarize recent advancements in the development of CDK8 inhibitors.
• To provide an outlook on the future of CDK8 inhibitors in cancer therapy.

Main Methods:

• Literature review of co-crystal structures (active and inactive states) of CDK8.
• Analysis of biological mechanisms underlying CDK8's role in cancer.
• Synthesis of recent research on CDK8 inhibitor development.

Main Results:

• Potent and selective CDK8 inhibitors have been discovered, aided by resolved crystal structures.
• CDK8's complex and context-dependent role in cancer progression is further elucidated.
• Significant progress has been made in identifying and developing targeted CDK8 inhibitors.

Conclusions:

• CDK8 inhibitors represent a promising avenue for novel cancer therapeutics.
• Understanding CDK8's context-dependent functions is crucial for effective therapeutic strategies.
• Continued research into CDK8 inhibitors holds potential for future cancer treatment advancements.