Journal
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
Volume 58, Issue 19, Pages 6321-6326Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.201901336
Keywords
cancer; cell cycle; CDK4/6; drug design; protein degradation
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Funding
- Damon Runyon Cancer Research Fellowship [DRG-2270-16]
- NIH [R01CA218278]
- Damon Runyon Cancer Research Foundation [DRR-50-18]
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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.
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