Abstract

Cyclin-dependent kinases (CDKs) are central regulators of the cell cycle progression and transcription, making them attractive targets especially in oncology. The clinical success of CDK4/6 inhibitors in hormone receptor-positive (HR+) and HER2-negative (HER2-) breast cancer has highlighted the therapeutic potential of CDK inhibition, along with ongoing clinical evaluation of other CDK-targeted agents. Despite the progress, challenges still remain due to off-target toxicity and the emergence of resistance. Recently, macrocycle-based drug design has gained recognition for its ability to enhance the kinase inhibitory activities and selectivity, improve drug-like properties, and potentially overcome resistance. This review summarizes recent advances (2015-2025) in macrocyclization strategies for CDK inhibitors, tracing the structural modification process from the acyclic scaffolds and highlighting their potential to address key limitations of current therapies.

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Year
2025
Type
article
Volume
17
Issue
24
Pages
3057-3070
Citations
0
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Jiamin Zheng, Zhisen Zhang, Jinxin Liu et al. (2025). Recent advance in macrocyclic CDK inhibitors. Future Medicinal Chemistry , 17 (24) , 3057-3070. https://doi.org/10.1080/17568919.2025.2599648

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DOI
10.1080/17568919.2025.2599648