Binding patterns and structure-activity relationship of CDK8 inhibitors.
Duo Ma1, Xing Chen1, Xiao-Bao Shen2
1School of Pharmacy, Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, Anhui Medical University, Hefei 230032, PR China.
Bioorganic Chemistry
|February 21, 2020
Summary
Cyclin-dependent kinase 8 (CDK8) is a promising cancer target. This review summarizes CDK8 inhibitors, aiding the development of more selective cancer drugs.
Area of Science:
- Medicinal Chemistry
- Oncology
- Structural Biology
Background:
- Cyclin-dependent kinase 8 (CDK8) is an emerging therapeutic target for various cancers, including colorectal, breast, melanoma, and prostate.
- The crystal structure of CDK8 has been elucidated, revealing potential binding sites for inhibitors.
- Eutectic interactions have been identified for 24 known CDK8-targeting compounds.
Purpose of the Study:
- To consolidate information on CDK8 inhibitors to guide the development of novel therapeutic agents.
- To provide a reference for medicinal chemists focusing on CDK8 inhibitor design, emphasizing improved selectivity.
- To analyze structure-activity relationships and binding data of existing CDK8 inhibitors.
Main Methods:
- Literature review and data compilation on CDK8 inhibitors.
- Analysis of published crystal structures of CDK8.
- Summary of structure-activity relationships (SAR) and binding data for identified compounds.
Main Results:
- Identification and characterization of 24 compounds exhibiting eutectic interactions with CDK8.
- Detailed summary of the structural features and activity profiles of representative CDK8 inhibitors.
- Analysis of SAR trends and binding modes for various inhibitor classes.
Conclusions:
- CDK8 is a validated target for multiple cancer types.
- Understanding the structure, SAR, and binding of current inhibitors is crucial for designing next-generation CDK8-targeted cancer therapies.
- This review serves as a valuable resource for researchers aiming to develop more selective and effective CDK8 inhibitors.
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