GSE138894 Imipridone anticancer compounds ectopically activate the ClpP protease and represent a new scaffold for antibiotic development

Contributors : Samuel Jacques ; Almer M van der Sloot ; Caroline Huard ; Jasmin Coulombe-Huntington ; Sarah Tsao ; Sylvain Tollis ; Thierry Bertomeu ; Elizabeth J Culp ; Daniel Pallant ; Michael A Cook ; Eric Bonneil ; Pierre Thibault ; Gerard D Wright ; Michael TyersSeries Type : OtherOrganism : Homo sapiensSystematic genetic interaction profiles can reveal the mechanism-of-action of bioactivecompounds. The imipridone ONC201, which is currently in cancer clinical trials, has beenascribed a variety of different targets. To investigate the genetic dependencies of imipridoneaction, we screened a genome-wide CRISPR knockout library in the presence of either ONC201or its more potent analog ONC212. Loss of the mitochondrial matrix protease CLPP or themitochondrial intermediate peptidase MIPEP conferred strong resistance to both compounds.Biochemical and surrogate genetic assays showed that impridones directly activate CLPP andthat MIPEP is necessary for proteolytic maturation of CLPP into a catalytically competent form.Quantitative proteomic analysis of cells treated with ONC212 revealed degradation of manymitochondrial as well as non-mitochondrial proteins. Prompted by the conservation of ClpPfrom bacteria to humans, we found that the imipridones also activate ClpP from Escherichiacoli, B. subtilis and Staphylococcus aureus in biochemical and genetic assays. ONC212 andacyldepsipeptide (ADEP)-4, a known activator of bacterial ClpP, caused similar proteome-widedegradation...
Source: GEO: Gene Expression Omnibus - Category: Genetics & Stem Cells Tags: Other Homo sapiens Source Type: research