2. Academic Validation
  3. Discovery of novel flavonoid-based CDK9 degraders for prostate cancer treatment via a PROTAC strategy

Discovery of novel flavonoid-based CDK9 degraders for prostate cancer treatment via a PROTAC strategy

  • Eur J Med Chem. 2023 Nov 15;260:115774. doi: 10.1016/j.ejmech.2023.115774.
Tizhi Wu 1,  Zhiming Zhang 1,  Guangyue Gong 1,  Zekun Du 1,  Yifan Xu 1,  Sixian Yu 1,  Feihai Ma 1,  Xuan Zhang 1,  Yuxiao Wang 1,  Haoming Chen 1,  Shiqi Wu 1,  Xi Xu 1,  Zhixia Qiu 1,  Zhiyu Li 1,  Hongxi Wu 2,  Jinlei Bian 3,  Jubo Wang 4
Affiliations

Affiliations

  • 1 Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, PR China.
  • 2 Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, PR China. Electronic address: whx@cpu.edu.cn.
  • 3 Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, PR China. Electronic address: bianjl@cpu.edu.cn.
  • 4 Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, PR China. Electronic address: 1620194588@cpu.edu.cn.
PMID: 37672930 DOI: 10.1016/j.ejmech.2023.115774
Abstract

CDK9 plays a vital role in regulating RNA transcription and significantly impacts the expression of short-lived proteins such as Mcl-1 and c-Myc. Thus, targeting CDK9 holds great promise for the development of antitumor drugs. Natural flavonoid derivatives have recently gained considerable attention in the field of antitumor drug research due to their broad bioactivity and low toxicity. In this study, the PROTAC strategy was used to perform structural modifications of the flavonoid derivative LWT-111 to design a series of flavonoid-based CDK9 degraders. Notably, compound CP-07 emerged as a potent CDK9 degrader, effectively suppressing the proliferation and colony formation of 22RV1 cells by downregulating Mcl-1 and c-Myc. Moreover, CP-07 exhibited significant tumor growth inhibition with a TGI of 75.1% when administered at a dose of 20 mg/kg in the 22RV1 xenograft tumor model. These findings demonstrated the potential of CP-07 as a powerful flavonoid-based CDK9 degrader for prostate Cancer therapy.

Keywords

CDK9 degrader; Flavonoid derivatives; PROTACs; Prostate cancer therapy.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-149495
    PROTAC CDK9 Degrader