2. Academic Validation
  3. Development of selective mono or dual PROTAC degrader probe of CDK isoforms

Development of selective mono or dual PROTAC degrader probe of CDK isoforms

  • Eur J Med Chem. 2020 Feb 1;187:111952. doi: 10.1016/j.ejmech.2019.111952.
Fei Zhou 1,  Luyu Chen 1,  Chaoguo Cao 1,  Jiang Yu 1,  Xiaojiao Luo 1,  Peiting Zhou 1,  Lifeng Zhao 2,  Wu Du 3,  Jijun Cheng 3,  Yongmei Xie 1,  Yuanwei Chen 4
Affiliations

Affiliations

  • 1 State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, 610041, China.
  • 2 Sichuan Industrial Institute of Antibiotics, Chengdu University, Chengdu, 610052, China.
  • 3 Hinova Pharmaceuticals Inc, 4th Floor, Building RongYao A, No. 5, Keyuan South Road, Chengdu, 610041, China.
  • 4 State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, 610041, China; Hinova Pharmaceuticals Inc, 4th Floor, Building RongYao A, No. 5, Keyuan South Road, Chengdu, 610041, China. Electronic address: ywchen@scu.edu.cn.
PMID: 31846828 DOI: 10.1016/j.ejmech.2019.111952
Abstract

Cyclin-dependent kinase (CDK) family members are promising molecular targets in discovering potent inhibitors in disease settings, they function differentially. CDK2, CDK4 and CDK6, directly regulate the cell cycle, while CDK9 primarily modulates the transcription regulation. In discovering inhibitors of these CDKs, toxicity associated with off-target effect on other CDK homologs often posts as a clinical issue and hinders their further therapeutic development. To improve efficacy and reduce toxicity, here, using the Proteolysis Targeted Chimeras (PROTACs) approach, we design and further optimize small molecule degraders targeting multiple CDKs. We showed that heterobifunctional compound A9 selectively degraded CDK2. We also identified a dual-degrader, compound F3, which potently induced degradation of both CDK2 (DC50: 62 nM) and CDK9 (DC50: 33 nM). In human prostate Cancer PC-3 cells, compound F3 potently inhibits cell proliferation by effectively blocking the cell cycle in S and G2/M phases. Our preliminary data suggests that PROTAC-oriented CDK2/9 degradation is potentially an effective therapeutic approach.

Keywords

CDK2; CDK9; Cell cycle; PROTAC; Prostate cancer.

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