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

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 ca...

Full description

Saved in:
Bibliographic Details
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
Citations: Items that this one cites
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:1860-7179
1860-7187
DOI:10.1002/cmdc.202400528