2. Academic Validation
  3. Discovery of Dehydrogenated Imipridone Derivatives as Activators of Human Caseinolytic Protease P

Discovery of Dehydrogenated Imipridone Derivatives as Activators of Human Caseinolytic Protease P

  • J Med Chem. 2024 Sep 12;67(17):15328-15352. doi: 10.1021/acs.jmedchem.4c00798.
Jinxin Jiang 1,  Guangjun Xie 2,  Tong Li 2,  Hao Ding 1,  Rui Tang 2,  Jiajun Luo 2,  Qiannan Li 1,  Wugang Lu 3,  Yibei Xiao 1 4,  Haiying Sun 2
Affiliations

Affiliations

  • 1 State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
  • 2 Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China.
  • 3 School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China.
  • 4 Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
PMID: 39172943 DOI: 10.1021/acs.jmedchem.4c00798
Abstract

Based on the founding member of imipridones, ONC201, a class of dehydrogenated imipridone derivatives was designed, synthesized, and evaluated in a series of biochemical and biological assays as human caseinolytic protease P (hClpP) activators. Mechanism studies for one of the most potent compounds, XT6, indicated that it can potently bind to both recombinant and cellular hClpP, effectively promote the formation of hClpP tetradecamer, efficiently induce the degradation of hClpP substrates, robustly upregulate the expression of ATF4, and strongly inhibit the phosphorylations of Akt and ERK. More importantly, XT6 exhibited a promising pharmacokinetic profile in rats and could penetrate the blood brain barrier. It showed highly potent in vivo antitumor activity in a MIAPACA2 cell line derived pancreatic Cancer model in BALB/c nude mice.

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