biostudies-literaturePolachova EAkademie Ved Cesk? RepublikyDeutsche ForschungsgemeinschaftMinisterstvo ?kolstv?, Ml?de?e a Telov?chovyEuropean Regional Development Fund251-265https://www.ebi.ac.uk/biostudies/studies/S-EPMC9841525biostudies-literatureUnknown66(1)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 demonstratesJournal of medicinal chemistryChemical Blockage of the Mitochondrial Rhomboid Protease PARL by Novel Ketoamide Inhibitors Reveals Its Role in PINK1/Parkin-Dependent Mitophagy.PMC9841525Le2749/1-2 263531414/FOR2290LO1302RVO 61388963CZ.02.1.01/0.0/0.0/16_019/0000729Polachova ETicha AStrisovsky KMajer PHeuten ELampe PBach KLanger TStanchev SLemberg MKfalseChemical Blockage of the Mitochondrial Rhomboid Protease PARL by Novel Ketoamide Inhibitors Reveals Its Role in PINK1/Parkin-Dependent Mitophagy.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 demonstrates2023-01-01T00:00:00Z2023 Jan2026-07-14T17:05:52.037Z2025-04-06T13:12:31.369ZS-EPMC98415253654094210.1021/acs.jmedchem.2c01092