期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 62, 期 16, 页码 7575-7582出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.9b00871
关键词
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资金
- National Natural Science Foundation of China [81573277, 81622042, 81773567, 81672950]
- National Major Scientific and Technological Special Project for Significant New Drugs Development [SQ2017ZX095003]
- NIH Cancer Center Support Grant (CCSG) [P30 CA08748]
- Breast Cancer Research Foundation
A focused PROTAC library hijacking cancer therapeutic target CDK6 was developed. A design principle as match/mismatch was proposed for understanding the degradation profile differences in these PROTACs. Notably, potent PROTACs with specific and remarkable CDK6 degradation potential were generated by linking CDK6 inhibitor palbociclib and E3 ligase CRBN recruiter pomalidomide. The PROTAC strongly inhibited proliferation of hematopoietic cancer cells including multiple myeloma and robustly degraded copy-amplified/mutated forms of CDK6, indicating future potential clinical applications.
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