Potent and Preferential Degradation of CDK6 Via Proteolysis Targeting Chimera Degraders

Overview

Journal J Med Chem

Publisher American Chemical Society

Specialty Chemistry

Date 2019 Jul 23

PMID 31330105

Citations 65

Authors

Shang Su

Zimo Yang

Hongying Gao

Haiyan Yang

Songbiao Zhu

Zixuan An

Juanjuan Wang

Qing Li

Sarat Chandarlapaty

Haiteng Deng

Wei Wu

Yu Rao

Affiliations

Soon will be listed here.

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.

Citing Articles

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Resistance mechanisms and therapeutic strategies of CDK4 and CDK6 kinase targeting in cancer.

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