Discovery of small molecule degraders for modulating cell cycle

Abstract

The cell cycle is a complex process that involves DNA replication, protein expression, and cell division. Dysregulation of the cell cycle is associated with various diseases. Cyclin-dependent kinases (CDKs) and their corresponding cyclins are major proteins that regulate the cell cycle. In contrast to inhibition, a new approach called proteolysis-targeting chimeras (PROTACs) and molecular glues can eliminate both enzymatic and scaffold functions of CDKs and cyclins, achieving targeted degradation. The field of PROTACs and molecular glues has developed rapidly in recent years. In this article, we aim to summarize the latest developments of CDKs and cyclin protein degraders. The selectivity, application, validation and the current state of each CDK degrader will be overviewed. Additionally, possible methods are discussed for the development of degraders for CDK members that still lack them. Overall, this article provides a comprehensive summary of the latest advancements in CDK and cyclin protein degraders, which will be helpful for researchers working on this topic.

Keywords

PROTAC / molecular glue / degrader / cell cycle / CDK / cyclin

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Acknowledgements

This work was supported by National Key R&D Program of China (Nos. 2021YFA1302100, 2020YFE0202200, and 2021YFA1300200), National Natural Science Foundation of China (No. 82125034), Fellowship of China Postdoctoral Science Foundation (No. 2021M701953), and the Foundation of Shuimu Tsinghua Scholar Program (No. 2021SM110).

Compliance with ethics guidelines

Conflicts of interest Liguo Wang, Zhouli Yang, Guangchen Li, Yongbo Liu, Chao Ai, and Yu Rao declare no conflict interests.

This manuscript is a review article and does not involve a research protocol requiring approval by the relevant institutional review board or ethics committee.

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