{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Xu Z"],"funding":["NIH HHS"],"pagination":["21377-21393"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC12700136"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["68(20)"],"pubmed_abstract":["Cancer cells depend on mitochondrial reprogramming for growth, but this raises reactive oxygen species (ROS), increasing reliance on protein quality control (PQC) repair mechanisms. The mitochondrial proteome is maintained through a robust PQC composed of chaperones and proteases, including the mitochondrial matrix protease caseinolytic protease P (ClpP). ClpP has recently emerged as a potential therapeutic target against cancer. Notably, imipridones act as ClpP agonists and have shown potent anticancer activity by inhibiting mitochondrial Electron Transport Chain (ETC) function. In this study, we developed a new generation ClpP agonist, compound <b>9</b> (MS6076), which exhibits enhanced ClpP binding, more potent disruption of mitochondrial ETC and lethality in breast cancer models compared to the imipridone ONC212. Furthermore, we show that compound <b>9</b> induced cell death in cancer cells resistant to ONC212. The discovery and characterization of compound <b>9</b> therefore add to the expanding arsenal of imipridones to target ClpP in cancer."],"journal":["Journal of medicinal chemistry"],"pubmed_title":["Targeting the Mitochondrial Protease ClpP for Anticancer Therapy."],"pmcid":["PMC12700136"],"funding_grant_id":["S10 OD025132","S10 OD028504"],"pubmed_authors":["Germain D","Chattopadhyay M","Kaniskan HU","Pokushalov D","Choo C","Lee Y","Kabir M","Jin J","Xu Z","Jenkins EC"],"additional_accession":[]},"is_claimable":false,"name":"Targeting the Mitochondrial Protease ClpP for Anticancer Therapy.","description":"Cancer cells depend on mitochondrial reprogramming for growth, but this raises reactive oxygen species (ROS), increasing reliance on protein quality control (PQC) repair mechanisms. The mitochondrial proteome is maintained through a robust PQC composed of chaperones and proteases, including the mitochondrial matrix protease caseinolytic protease P (ClpP). ClpP has recently emerged as a potential therapeutic target against cancer. Notably, imipridones act as ClpP agonists and have shown potent anticancer activity by inhibiting mitochondrial Electron Transport Chain (ETC) function. In this study, we developed a new generation ClpP agonist, compound <b>9</b> (MS6076), which exhibits enhanced ClpP binding, more potent disruption of mitochondrial ETC and lethality in breast cancer models compared to the imipridone ONC212. Furthermore, we show that compound <b>9</b> induced cell death in cancer cells resistant to ONC212. The discovery and characterization of compound <b>9</b> therefore add to the expanding arsenal of imipridones to target ClpP in cancer.","dates":{"release":"2025-01-01T00:00:00Z","publication":"2025 Oct","modification":"2026-06-06T02:16:31.053Z","creation":"2026-05-24T03:12:18.199Z"},"accession":"S-EPMC12700136","cross_references":{"pubmed":["41032690"],"doi":["10.1021/acs.jmedchem.5c01315"]}}