Development of dual and selective degraders of cyclin‐dependent kinases 4 and 6

Cyclin‐dependent kinases 4 and 6 (CDK4/6) are key regulators of the cell cycle, and CDK4/6 inhibitors are FDA‐approved 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), 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 exhibited enhanced anti‐proliferative effects compared to CDK4/6 inhibition, CDK4/6 degradation, or IKZF1/3 degradation. In sum, we report here the first compounds capable of inducing selective degradation of CDK4 and CDK6 as tools to pharmacologically dissect their distinct biological functions.

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