通过蛋白水解靶向嵌合体降解剂有效且特异地降解 CDK6。
Potent and Preferential Degradation of CDK6 via Proteolysis Targeting Chimera Degraders.
机构信息
MOE Key Laboratory of Protein Sciences, School of Life Sciences , Tsinghua University , Beijing 100084 , P. R. China.
MOE Key Laboratory of Protein Sciences, School of Pharmaceutical Sciences, MOE Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology , Tsinghua University , Beijing 100084 , P. R. China.
出版信息
J Med Chem. 2019 Aug 22;62(16):7575-7582. doi: 10.1021/acs.jmedchem.9b00871. Epub 2019 Aug 2.
Abstract
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.
摘要
开发了一种针对癌症治疗靶标 CDK6 的靶向 PROTAC 文库。提出了一种“匹配/不匹配”的设计原则，用于理解这些 PROTAC 降解谱的差异。值得注意的是，通过连接 CDK6 抑制剂 palbociclib 和 E3 连接酶 CRBN 招募剂 pomalidomide，生成了具有特异性和显著 CDK6 降解潜力的强效 PROTAC。该 PROTAC 强烈抑制包括多发性骨髓瘤在内的造血癌细胞的增殖，并强烈降解 CDK6 的拷贝扩增/突变形式，表明其具有未来的临床应用潜力。
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