2. Academic Validation
  3. Thermal proteome profiling identifies the membrane-bound purinergic receptor P2X4 as a target of the autophagy inhibitor indophagolin

Thermal proteome profiling identifies the membrane-bound purinergic receptor P2X4 as a target of the autophagy inhibitor indophagolin

  • Cell Chem Biol. 2021 Dec 16;28(12):1750-1757.e5. doi: 10.1016/j.chembiol.2021.02.017.
Marjorie A Carnero Corrales 1,  Sarah Zinken 1,  Georgios Konstantinidis 2,  Muhammad Rafehi 3,  Aliaa Abdelrahman 3,  Yao-Wen Wu 2,  Petra Janning 1,  Christa E Müller 3,  Luca Laraia 4,  Herbert Waldmann 5
Affiliations

Affiliations

  • 1 Max Planck Institute of Molecular Physiology, Department of Chemical Biology, Otto-Hahn-Straße 11, 44227 Dortmund, Germany; Technische Universität Dortmund, Faculty of Chemistry and Chemical Biology, Otto-Hahn-Straße 6, 44227 Dortmund, Germany.
  • 2 Chemical Genomics Center of the Max Planck Society, Otto-Hahn-Straße 15, 44227 Dortmund, Germany; Department of Chemistry, Umeå University, 90187 Umeå, Sweden.
  • 3 PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Sciences Bonn (PSB), Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany.
  • 4 Max Planck Institute of Molecular Physiology, Department of Chemical Biology, Otto-Hahn-Straße 11, 44227 Dortmund, Germany; Department of Chemistry, Technical University of Denmark, Kemitorvet 207, Room 124, 2800 Kongens Lyngby, Denmark. Electronic address: luclar@kemi.dtu.dk.
  • 5 Max Planck Institute of Molecular Physiology, Department of Chemical Biology, Otto-Hahn-Straße 11, 44227 Dortmund, Germany; Technische Universität Dortmund, Faculty of Chemistry and Chemical Biology, Otto-Hahn-Straße 6, 44227 Dortmund, Germany. Electronic address: herbert.waldmann@mpi-dortmund.mpg.de.
PMID: 33725479 DOI: 10.1016/j.chembiol.2021.02.017
Abstract

Signaling pathways are frequently activated through signal-receiving membrane proteins, and the discovery of small molecules targeting these receptors may yield insights into their biology. However, due to their intrinsic properties, membrane protein targets often cannot be identified by means of established approaches, in particular affinity-based proteomics, calling for the exploration of new methods. Here, we report the identification of indophagolin as representative member of an indoline-based class of Autophagy inhibitors through a target-agnostic phenotypic assay. Thermal proteome profiling and subsequent biochemical validation identified the purinergic receptor P2X4 as a target of indophagolin, and subsequent investigations suggest that indophagolin targets further purinergic receptors. These results demonstrate that thermal proteome profiling may enable the de novo identification of membrane-bound receptors as cellular targets of bioactive small molecules.

Keywords

autophagy; biological chemistry and chemical biology; proteomics; target identification; thermal proteome profiling.

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