2. Academic Validation
  3. Phenotypic Assay Leads to Discovery of Mitophagy Inducers with Therapeutic Potential for Parkinson's Disease

Phenotypic Assay Leads to Discovery of Mitophagy Inducers with Therapeutic Potential for Parkinson's Disease

  • ACS Chem Neurosci. 2021 Dec 15;12(24):4512-4523. doi: 10.1021/acschemneuro.1c00529.
Inés Maestro 1 2,  Laura R de la Ballina 3 4,  Anne Simonsen 3 4,  Patricia Boya 1,  Ana Martinez 1 2
Affiliations

Affiliations

  • 1 Centro de Investigaciones Biologicas Margarita Salas-CSIC, Ramiro de Maeztu 9, 28040 Madrid, Spain.
  • 2 Centro de Investigacion Biomedica en Red en Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, 28031 Madrid, Spain.
  • 3 Department of Molecular Medicine, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, 0372 Oslo, Norway.
  • 4 Centre for Cancer Cell Reprogramming, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, 0450 Oslo, Norway.
PMID: 34846852 DOI: 10.1021/acschemneuro.1c00529
Abstract

Mitophagy, the selective degradation of mitochondria by Autophagy, involved in important physiological processes and defects in pathways has been reported in pathological conditions, such as neurodegeneration. Thus, Mitophagy is an interesting target for drug discovery programs. In this investigation, we used robust phenotypic assay to screen a set of 50 small heterocyclic compounds to identify inducers of Mitophagy. We identified two compounds, VP07 and JAR1.39, that induce Parkin-dependent Mitophagy. Based on structure-activity relationship studies, we proposed the ability of the compounds to act as LIGHT chain 3 (LC3) interactors, similar to cardiolipin or ceramide, triggering Mitophagy via Pink1/Parkin. Finally, we show promising therapeutic applicability in a cellular model of Parkinson's disease.

Keywords

Parkinson’s disease; drug discovery; mitophagy; mitophagy inducers; phenotypic assay.

Figures
Products