2. Academic Validation
  3. First orally bioavailable prodrug of proteolysis targeting chimera (PROTAC) degrades cyclin-dependent kinases 2/4/6 in vivo

First orally bioavailable prodrug of proteolysis targeting chimera (PROTAC) degrades cyclin-dependent kinases 2/4/6 in vivo

  • Eur J Med Chem. 2021 Jan 1:209:112903. doi: 10.1016/j.ejmech.2020.112903.
Mingming Wei 1,  Rui Zhao 1,  Yuting Cao 1,  Yujiao Wei 1,  Ming Li 2,  Zhiqiang Dong 1,  Yulin Liu 1,  Hao Ruan 1,  Ying Li 1,  Sheng Cao 1,  Zhiwen Tang 1,  Yuanyuan Zhou 1,  Wei Song 1,  Yubo Wang 1,  Jiefu Wang 3,  Guang Yang 4,  Cheng Yang 5
Affiliations

Affiliations

  • 1 The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, Tianjin, 300071, PR China.
  • 2 Cangzhou Institutes for Food and Drug Control, Cangzhou, 061000, PR China.
  • 3 Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, PR China. Electronic address: jwang05@tmu.edu.cn.
  • 4 The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, Tianjin, 300071, PR China. Electronic address: Guang.yang@nankai.edu.cn.
  • 5 The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, Tianjin, 300071, PR China. Electronic address: Cheng.yang@nankai.edu.cn.
PMID: 33256948 DOI: 10.1016/j.ejmech.2020.112903
Abstract

A growing number of reports suggested that the inhibitor targeting cyclin-dependent kinases (CDK) 2/4/6 can act as a more feasible chemotherapy strategy. In the present paper, a novel PROTAC molecule was developed based on the structure of Ribociclib's derivative. In malignant melanoma cells, the degrader can not only degrade CDK 2/4/6 simultaneously and effectively, but also remarkably induce cell cycle arrest and Apoptosis of melanoma cells. Moreover, PROTAC molecules with CRBN ligands always have poor oral bioavailability. We developed the orally bioavailable prodrug for the first time. It would provide general solution for oral administration of the PROTAC molecules, derived from CRBN ligands, for animal test conveniently.

Keywords

Anti-tumor; CDK 2/4/6; Orally bioavailable prodrug; PROTAC.

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