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Potent and Preferential Degradation of CDK6 via Proteolysis Targeting Chimera Degraders.

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.

SUBMITTER: Su S 

PROVIDER: S-EPMC6790125 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Potent and Preferential Degradation of CDK6 via Proteolysis Targeting Chimera Degraders.

Su Shang S   Yang Zimo Z   Gao Hongying H   Yang Haiyan H   Zhu Songbiao S   An Zixuan Z   Wang Juanjuan J   Li Qing Q   Chandarlapaty Sarat S   Deng Haiteng H   Wu Wei W   Rao Yu Y  

Journal of medicinal chemistry 20190802 16

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 degra  ...[more]

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