Recent development of CDK inhibitors: An overview of CDK/inhibitor co-crystal structures
Weiyan Cheng1, Zhiheng Yang1, Suhua Wang1
1Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China; Henan Key Laboratory of Precision Clinical Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.
Abstract:
The cyclin-dependent protein kinases (CDKs) are protein-serine/threonine kinases that display crucial effects in regulation of cell cycle and transcription. While the excessive expression of CDKs is intimate related to the development of diseases including cancers, which provides opportunities for disease treatment. A large number of small molecules are explored targeting CDKs. CDK/inhibitor co-crystal structures play an important role during the exploration of inhibitors. So far nine kinds of CDK/inhibitor co-crystals have been determined, they account for the highest proportion among the Protein Data Bank (PDB) deposited crystal structures. Herein, we review main co-crystals of CDKs in complex with corresponding inhibitors reported in recent years, focusing our attention on the binding models and the pharmacological activities of inhibitors.
Insights
Cyclin-dependent kinases (CDKs) regulate cell cycles and transcription. Reviewing CDK/inhibitor co-crystal structures aids in developing small molecule drugs for cancer treatment.
Area of Science:
- Biochemistry and Molecular Biology
- Structural Biology
- Pharmacology
Background:
- Cyclin-dependent kinases (CDKs) are key regulators of the cell cycle and transcription.
- Aberrant CDK expression is linked to diseases like cancer, presenting therapeutic targets.
- Small molecule inhibitors targeting CDKs are actively researched for disease treatment.
Purpose of the Study:
- To review recent CDK/inhibitor co-crystal structures.
- To analyze inhibitor binding models within these co-crystals.
- To correlate structural findings with the pharmacological activities of inhibitors.
Main Methods:
- Literature review of CDK/inhibitor co-crystal structures.
- Analysis of crystallographic data from the Protein Data Bank (PDB).
- Examination of inhibitor binding modes and their impact on kinase activity.
Main Results:
- Nine types of CDK/inhibitor co-crystals represent a significant portion of PDB entries.
- Detailed binding models for various inhibitors complexed with CDKs have been elucidated.
- Structure-activity relationships are being established for novel CDK inhibitors.
Conclusions:
- CDK/inhibitor co-crystal structures are vital for rational drug design.
- Understanding binding interactions facilitates the development of targeted cancer therapies.
- This review highlights the importance of structural information in advancing CDK inhibitor discovery.
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