Recent advances in regulating the cell cycle through inhibiting CDKs for cancer treatment
Weijiao Chen1, Xujie Zhuang1, Yuanyuan Chen1
1State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China.
Abstract:
The inhibition of cyclin-dependent kinases (CDKs) is considered a promising strategy for cancer treatment due to their role in cell cycle regulation. However, CDK inhibitors with no selectivity among CDK families have not been approved. A CDK inhibitor with high selectivity for CDK4/6 exhibited significant treatment effects on breast cancer and has become a heavy bomb on the market. Subsequently, resistance gradually decreased the efficacy of selective CDK4/6 inhibitors in breast cancer treatment. In this review, we first introduce the development of selective CDK4/6 inhibitors and then explain the role of CDK2 activation in inducing resistance to CDK4/6 inhibitors. Moreover, we focused on the development of CDK2/4/6 inhibitors and selective CDK2 inhibitors, which will aid in the discovery of novel CDK inhibitors targeting the cell cycle in the future.
Insights
Cyclin-dependent kinase (CDK) inhibitors targeting CDK4/6 show promise in breast cancer but face resistance. Activating CDK2 contributes to this resistance, driving research into new CDK2/4/6 inhibitors.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Cyclin-dependent kinases (CDKs) regulate the cell cycle and are key targets for cancer therapy.
- Selective CDK4/6 inhibitors have shown efficacy in breast cancer but acquired resistance limits their long-term use.
- CDK2 activation is increasingly recognized as a mechanism of resistance to CDK4/6 inhibitors.
Purpose of the Study:
- To review the development of selective CDK4/6 inhibitors.
- To elucidate the role of CDK2 activation in mediating resistance to CDK4/6 inhibitors.
- To highlight the emerging therapeutic strategies involving CDK2/4/6 inhibitors and selective CDK2 inhibitors.
Main Methods:
- Literature review of preclinical and clinical studies on CDK inhibitors.
- Analysis of molecular mechanisms underlying resistance to CDK4/6 inhibitors, focusing on CDK2.
- Synthesis of current research on novel CDK inhibitor development.
Main Results:
- Selective CDK4/6 inhibitors have demonstrated significant clinical benefits in breast cancer.
- CDK2 reactivation is a critical factor in the development of resistance to CDK4/6 inhibitors.
- Targeting CDK2, either alone or in combination with CDK4/6, represents a promising strategy to overcome resistance.
Conclusions:
- Understanding CDK2's role in resistance is crucial for advancing cancer therapy.
- The development of dual CDK2/4/6 inhibitors and selective CDK2 inhibitors offers potential solutions to overcome acquired resistance.
- Future research should focus on developing novel CDK inhibitors to improve patient outcomes in cell cycle-related cancers.
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