Development of Dual and Selective Degraders of Cyclin‐Dependent Kinases 4 and 6

作者：Baishan Jiang, Eric S. Wang, Katherine A. Donovan, Yanke Liang, Eric S. Fischer, Tinghu Zhang, Nathanael S. Gray · 发表于：Angewandte Chemie International Edition · 年份：2019 · DOI：10.1002/anie.201901336 · 被引用次数：268 · 研究领域：Protein Degradation and Inhibitors、Ubiquitin and proteasome pathways、Cancer-related Molecular Pathways

Cyclin-dependent kinases 4 and 6 (CDK4/6) are key regulators of the cell cycle, and there are FDA-approved CDK4/6 inhibitors for treating patients with metastatic breast cancer. However, due to conservation of their ATP-binding sites, development of selective agents has remained elusive. Here, we report imide-based degrader molecules capable of degrading both CDK4/6, or selectively degrading either CDK4 or CDK6. We were also able to tune the activity of these molecules against Ikaros (IKZF1) and Aiolos (IKZF3), which are well-established targets of imide-based degraders. We found that in mantle cell lymphoma cell lines, combined IKZF1/3 degradation with dual CDK4/6 degradation produced enhanced anti-proliferative effects compared to CDK4/6 inhibition, CDK4/6 degradation, or IKZF1/3 degradation. In summary, we report here the first compounds capable of inducing selective degradation of CDK4 and CDK6 as tools to pharmacologically dissect their distinct biological functions.