Discovery of novel CDK8 inhibitors using multiple crystal structures in docking-based virtual screening

Area of Science:

• Medicinal Chemistry
• Structural Biology
• Cancer Biology

Background:

• Cyclin-dependent kinase 8 (CDK8) is part of the Mediator complex and linked to cancer progression.
• CDK8 activation correlates with β-catenin signaling in colon and gastric cancers.

Purpose of the Study:

• To identify novel, potent inhibitors of CDK8 using computational methods.
• To explore structure-based drug design strategies for CDK8.

Main Methods:

• Docking-based virtual screening (VS) against multiple CDK8 crystal structures.
• 2D similarity searches to identify potential inhibitor derivatives.
• In vitro dose-response assays to determine IC50 values.

Main Results:

• Virtual screening successfully identified potent CDK8 inhibitors.
• Compounds W-34, W-37, W-8, and WS-2 exhibited IC50 values in the nanomolar range (6.5 nM, 36 nM, 93 nM, 9 nM, respectively).
• Multiple crystal structures improved the VS enrichment by accounting for protein flexibility.

Conclusions:

• The identified compounds serve as promising starting points for developing selective and potent CDK8 inhibitors.
• This study highlights the utility of docking-based VS with diverse protein conformations for drug discovery.