2. Academic Validation
  3. Potent and Preferential Degradation of CDK6 via Proteolysis Targeting Chimera Degraders

Potent and Preferential Degradation of CDK6 via Proteolysis Targeting Chimera Degraders

  • J Med Chem. 2019 Aug 22;62(16):7575-7582. doi: 10.1021/acs.jmedchem.9b00871.
Shang Su 1,  Zimo Yang 2,  Hongying Gao 1 2,  Haiyan Yang 1,  Songbiao Zhu 3,  Zixuan An 1,  Juanjuan Wang 1,  Qing Li 4,  Sarat Chandarlapaty 4,  Haiteng Deng 3,  Wei Wu 1,  Yu Rao 2
Affiliations

Affiliations

  • 1 MOE Key Laboratory of Protein Sciences, School of Life Sciences , Tsinghua University , Beijing 100084 , P. R. China.
  • 2 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.
  • 3 MOE Key Laboratory of Bioinformatics, School of Life Sciences , Tsinghua University , Beijing 100084 , P. R. China.
  • 4 Human Oncology and Pathogenesis Program , Memorial Sloan Kettering Cancer Center (MSKCC) , New York , New York 10065 , United States.
PMID: 31330105 DOI: 10.1021/acs.jmedchem.9b00871
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.

Figures
Products