Development of Small Molecular Hyper‐activators of Human Caseinolytic Peptidase P (hClpP) with a [1,8]‐naphthyridinone Scaffold as Novel Anti‐cancer Agents

• Published in: ChemMedChem 2025-02, Vol.20 (4), p.e202400528-n/a
• Main Authors: Fu, Yuantao, Yuan, Yinan, Tan, Rongliang, Jiang, Jinxin, Li, Zhilong, Li, Tong, Xie, Guangjun, Xiao, Yibei, Sun, Haiying
• Format: Article
• Language: English
• Subjects: Activator; Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; Bioavailability; Cancer; Cell Line, Tumor; Cell Proliferation - drug effects; Cellular stress response; Chemical synthesis; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; hClpP; Humans; Mice; Mitochondria; Molecular Structure; Naphthyridines - chemical synthesis; Naphthyridines - chemistry; Naphthyridines - pharmacology; Protein Degradation; Scaffolds; Small Molecule Libraries - chemical synthesis; Small Molecule Libraries - chemistry; Small Molecule Libraries - pharmacology; Structure-Activity Relationship; Substrate inhibition; Tumor cell lines
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.202400528

Based on a clinical staged small molecular hClpP activator ONC201, a class of novel hClpP agonists with a [1,8]naphthyridinone scaffold was designed, synthesized and evaluated in a series of biochemical and biological assays. Mechanism studies for the representative compound F20 indicated that it can potently bind to and activate hClpP, efficiently promote the degradation of hClpP substrates, robustly induce ATF4/CHOP regulated integrated stress responses, strongly inhibit cell growth and effectively induce apoptosis in a subset of cancer cell lines. F20 showed good PK profiles when dosed by intravenous injection and exhibited moderate oral bioavailability in mice. Based on a clinical staged anticancer agent ONC201, a class of novel hClpP activators containing a [1,8]‐naphthyridinone scaffold were designed, synthesized and evaluated in proteolysis and cell growth inhibition assays. The most potent compound F20 exhibited more potent activity that ONC201 in all these assays.