Imipridone Anticancer Compounds Ectopically Activate the ClpP Protease and Represent a New Scaffold for Antibiotic
Samuel Jacques1, Almer M van der Sloot2, Caroline C Huard1
1Institute for Research in Immunology and Cancer, University of Montréal, Quebec H3T 1JH, Canada.
Genetics
|February 26, 2020
Summary
Imipridones like ONC201 activate the mitochondrial protease CLPP, revealing new cancer drug mechanisms. This discovery also highlights imipridones as potential antibiotics against bacterial pathogens.
Area of Science:
- Molecular Biology
- Genetics
- Drug Discovery
Background:
- The imipridone ONC201, currently in cancer clinical trials, has multiple proposed targets.
- Understanding the precise mechanism of action for bioactive compounds is crucial for drug development.
Purpose of the Study:
- To elucidate the genetic dependencies and mechanism of action of imipridones ONC201 and ONC212.
- To explore the potential of imipridones as antibacterial agents.
Main Methods:
- Genome-wide CRISPR knockout screening in human cells treated with ONC201 or ONC212.
- Biochemical and genetic assays to assess CLPP protease activation and maturation.
- Quantitative proteomic analysis to identify protein degradation.
- Bacterial assays to evaluate imipridone activity against various species and antibiotic tolerance.
Main Results:
- Loss of mitochondrial CLPP protease or MIPEP peptidase conferred resistance to imipridones.
- Imipridones directly activate CLPP, requiring MIPEP for its functional maturation.
- ONC212 induced proteome-wide degradation in human cells.
- Imipridones activated bacterial ClpP and exhibited broad-spectrum antibacterial activity, including against antibiotic-tolerant bacteria.
- ONC212 enhanced rifampin's efficacy against *Staphylococcus aureus* persister cells.
Conclusions:
- Imipridone action in human cells is dependent on the mitochondrial CLPP protease pathway.
- The imipridone scaffold represents a novel class of antibacterial agents with potential applications in combating drug-resistant infections.
Keywords:
AAA+ ATPaseCLPPCRISPR screenMIPEPantibioticimipridonemitochondrionproteolysisproteomesynergismMore Related Videos
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