[en] The guanosine triphosphatase (GTPase) activity of the mitochondrial dynamin-related protein Optic Atrophy 1 (OPA1) regulates cristae remodeling, cytochrome c release, and apoptosis. Elevated OPA1 levels in multiple cancers correlate with reduced therapy sensitivity and poor survival, calling for specific OPA1 GTPase inhibitors. A high-throughput screening of ~10,000 compounds identified MYLS22, a heterocyclic N-pyrazole derivative as a reversible, noncompetitive OPA1 GTPase inhibitor. MYLS22 engaged with OPA1 in vitro and in cells where it induced cristae remodeling and mitochondrial fragmentation contingent on intactness of its predicted OPA1 binding site. MYLS22 enhanced proapoptotic cytochrome c release and sensitized breast adenocarcinoma cells to anti-Bcl-2 therapy, without toxicity on noncancer cells. By MYLS22 structure-activity relationship studies, we obtained Opa1 inhibitor 0 (Opitor-0) that inhibited OPA1, promoted cytochrome c release, and restored anti-Bcl-2 therapy sensitivity more efficiently than MYLS22. These chemical probes validate OPA1 as a therapeutic target to increase cancer cell apoptosis at the mitochondrial level.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Pellattiero, Anna ; Veneto Institute of Molecular Medicine, Via Orus 2, 35129 Padova, Italy ; Department of Biology, University of Padova, Via U. Bassi 58B, 35121 Padova, Italy
Quirin, Charlotte; Veneto Institute of Molecular Medicine, Via Orus 2, 35129 Padova, Italy ; Department of Biology, University of Padova, Via U. Bassi 58B, 35121 Padova, Italy
Magrin, Federico ; Veneto Institute of Molecular Medicine, Via Orus 2, 35129 Padova, Italy ; Department of Biology, University of Padova, Via U. Bassi 58B, 35121 Padova, Italy ; Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova, Italy
Sturlese, Mattia ; Molecular Modeling Section, Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova, Italy
Fracasso, Alberto ; Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova, Italy
Biris, Nikolaos ; Departments of Biochemistry and Medicine, Albert Einstein College of Medicine, Bronx, NY, USA
Herkenne, Stéphanie ; Université de Liège - ULiège > Département des sciences de la vie ; Veneto Institute of Molecular Medicine, Via Orus 2, 35129 Padova, Italy ; Department of Biology, University of Padova, Via U. Bassi 58B, 35121 Padova, Italy
Cendron, Laura ; Veneto Institute of Molecular Medicine, Via Orus 2, 35129 Padova, Italy
Gavathiotis, Evripidis ; Departments of Biochemistry and Medicine, Albert Einstein College of Medicine, Bronx, NY, USA
Moro, Stefano ; Molecular Modeling Section, Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova, Italy
Mattarei, Andrea ; Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova, Italy
Scorrano, Luca ; Veneto Institute of Molecular Medicine, Via Orus 2, 35129 Padova, Italy ; Department of Biology, University of Padova, Via U. Bassi 58B, 35121 Padova, Italy
Language :
English
Title :
Small molecule OPA1 inhibitors amplify cytochrome c release and reverse cancer cells resistance to Bcl-2 inhibitors.
Publication date :
04 July 2025
Journal title :
Science Advances
eISSN :
2375-2548
Publisher :
American Association for the Advancement of Science (AAAS), United States
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