2. Academic Validation
  3. Development of novel imipridone derivatives with potent anti-cancer activities as human caseinolytic peptidase P (hClpP) activators

Development of novel imipridone derivatives with potent anti-cancer activities as human caseinolytic peptidase P (hClpP) activators

  • Bioorg Chem. 2024 Aug 30:153:107765. doi: 10.1016/j.bioorg.2024.107765.
Yanzhi Zhang 1,  Jinxin Jiang 2,  Hao Ding 2,  Qiannan Li 2,  Yibei Xiao 3,  Haiying Sun 4
Affiliations

Affiliations

  • 1 Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China.
  • 2 State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China; Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
  • 3 State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China; Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China. Electronic address: yibei.xiao@cpu.edu.cn.
  • 4 Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China. Electronic address: haiyings1969@cpu.edu.cn.
PMID: 39243740 DOI: 10.1016/j.bioorg.2024.107765
Abstract

Based on a clinically staged small molecular hClpP activator ONC201, a class of imipridone derivatives was designed and synthesized. These compounds were evaluated in a protease hydrolytic assay, as well as cell growth inhibition assays in three Cancer cell lines, MIA PACA-2, HCT116, and MV4-11. A number of compounds that can more potently activate hClpP and more effectively inhibit cell growth in the three Cancer cell lines than ONC201 were identified. The most potent compound, ZYZ-17, activated hClpP with an EC50 value of 0.24 µM and inhibited the growth of the three Cancer cell lines with IC50 values of less than 10 nM. Mechanism studies for ZYZ-17 revealed that it potently activates cellular hClpP, efficiently induces the degradation of hClpP substrates, and robustly induces Apoptosis in the three Cancer cell lines. Furthermore, ZYZ-17 demonstrated a promising pharmacokinetic (PK) profile and exhibited highly potent in vivo antitumor activity in a pancreatic Cancer MIA PACA-2 xenograft model in BALB/c nude mice.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-168062
    ClpP激活剂
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