期刊
ACTA PHARMACEUTICA SINICA B
卷 11, 期 1, 页码 30-54出版社
INST MATERIA MEDICA, CHINESE ACAD MEDICAL SCIENCES
DOI: 10.1016/j.apsb.2020.05.001
关键词
CDK4/6; Cell cycle; Cancer; Selectivity; Drug resistance; PROTAC
资金
- Project Program of State Key Laboratory of Natural Medicines, China Pharmaceutical University (China) [SKLNMZZRC07]
- 111 Project (China) [B16046]
- Double First-Class University Project (China) [CPU2018GF04]
- Jiangsu Key Laboratory of Drug Design and Optimization (China) [DDORC201801]
- 65th China Postdoctoral Science Foundation [2019M652030]
CDK4/6 plays crucial roles in regulating the cell cycle and cancer cells, and selectively inhibiting CDK4/6 is an important strategy for cancer treatment. Several highly selective CDK4/6 inhibitors are currently in clinical trials, demonstrating a balance between anticancer efficacy and toxicity.
The sustained cell proliferation resulting from dysregulation of the cell cycle and activation of cyclin-dependent kinases (CDKs) is a hallmark of cancer. The inhibition of CDKs is a highly promising and attractive strategy for the development of anticancer drugs. In particular, third-generation CDK inhibitors can selectively inhibit CDK4/6 and regulate the cell cycle by suppressing the G1 to S phase transition, exhibiting a perfect balance between anticancer efficacy and general toxicity. To date, three selective CDK4/6 inhibitors have received approval from the U.S. Food and Drug Administration (FDA), and 15 CDK4/6 inhibitors are in clinical trials for the treatment of cancers. In this perspective, we discuss the crucial roles of CDK4/6 in regulating the cell cycle and cancer cells, analyze the rationale for selectively inhibiting CDK4/6 for cancer treatment, review the latest advances in highly selective CDK4/6 inhibitors with different chemical scaffolds, explain the mechanisms associated with CDK4/6 inhibitor resistance and describe solutions to overcome this issue, and briefly introduce proteolysis targeting chimera (PROTAC), a new and revolutionary technique used to degrade CDK4/6. (C) 2021 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.
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