{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Polachova E"],"funding":["Akademie Ved Cesk? Republiky","Deutsche Forschungsgemeinschaft","Ministerstvo ?kolstv?, Ml?de?e a Telov?chovy","European Regional Development Fund"],"pagination":["251-265"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC9841525"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["66(1)"],"pubmed_abstract":["The mitochondrial rhomboid protease PARL regulates mitophagy by balancing intramembrane proteolysis of PINK1 and PGAM5. It has been implicated in the pathogenesis of Parkinson's disease, but its investigation as a possible therapeutic target is challenging in this context because genetic deficiency of PARL may result in compensatory mechanisms. To address this problem, we undertook a hitherto unavailable chemical biology strategy. We developed potent PARL-targeting ketoamide inhibitors and investigated the effects of acute PARL suppression on the processing status of PINK1 intermediates and on Parkin activation. This approach revealed that PARL inhibition leads to a robust activation of the PINK1/Parkin pathway without major secondary effects on mitochondrial properties, which demonstrates"],"journal":["Journal of medicinal chemistry"],"pubmed_title":["Chemical Blockage of the Mitochondrial Rhomboid Protease PARL by Novel Ketoamide Inhibitors Reveals Its Role in PINK1/Parkin-Dependent Mitophagy."],"pmcid":["PMC9841525"],"funding_grant_id":["Le2749/1-2 263531414/FOR2290","LO1302","RVO 61388963","CZ.02.1.01/0.0/0.0/16_019/0000729"],"pubmed_authors":["Polachova E","Ticha A","Strisovsky K","Majer P","Heuten E","Lampe P","Bach K","Langer T","Stanchev S","Lemberg MK"],"additional_accession":[]},"is_claimable":false,"name":"Chemical Blockage of the Mitochondrial Rhomboid Protease PARL by Novel Ketoamide Inhibitors Reveals Its Role in PINK1/Parkin-Dependent Mitophagy.","description":"The mitochondrial rhomboid protease PARL regulates mitophagy by balancing intramembrane proteolysis of PINK1 and PGAM5. It has been implicated in the pathogenesis of Parkinson's disease, but its investigation as a possible therapeutic target is challenging in this context because genetic deficiency of PARL may result in compensatory mechanisms. To address this problem, we undertook a hitherto unavailable chemical biology strategy. We developed potent PARL-targeting ketoamide inhibitors and investigated the effects of acute PARL suppression on the processing status of PINK1 intermediates and on Parkin activation. This approach revealed that PARL inhibition leads to a robust activation of the PINK1/Parkin pathway without major secondary effects on mitochondrial properties, which demonstrates","dates":{"release":"2023-01-01T00:00:00Z","publication":"2023 Jan","modification":"2026-07-14T17:05:52.037Z","creation":"2025-04-06T13:12:31.369Z"},"accession":"S-EPMC9841525","cross_references":{"pubmed":["36540942"],"doi":["10.1021/acs.jmedchem.2c01092"]}}