2. Academic Validation
  3. The PAR2 inhibitor I-287 selectively targets Gαq and Gα12/13 signaling and has anti-inflammatory effects

The PAR2 inhibitor I-287 selectively targets Gαq and Gα12/13 signaling and has anti-inflammatory effects

  • Commun Biol. 2020 Nov 27;3(1):719. doi: 10.1038/s42003-020-01453-8.
Charlotte Avet 1,  Claudio Sturino 2 3,  Sébastien Grastilleur 4,  Christian Le Gouill 1,  Meriem Semache 1 5,  Florence Gross 1 5,  Louis Gendron 4,  Youssef Bennani 2 6,  Joseph A Mancini 2 7,  Camil E Sayegh 2 8,  Michel Bouvier 9
Affiliations

Affiliations

  • 1 Institute for Research in Immunology and Cancer, and Department of Biochemistry and Molecular Medicine, Université de Montréal, Montréal, QC, Canada, H3C 1J4.
  • 2 Vertex Pharmaceuticals (Canada), Inc., Laval, QC, Canada, H7V 4A7.
  • 3 Paraza Pharma, Inc., Saint-Laurent, QC, Canada, H4S 2E1.
  • 4 Département de Pharmacologie-Physiologie, Université de Sherbrooke, Centre de Recherche du CHU de Sherbrooke, Centre d'Excellence en Neurosciences de l'Université de Sherbrooke, Institut de Pharmacologie de Sherbrooke, Sherbrooke, QC, Canada, J1H 5N4.
  • 5 Domain Therapeutics North America, Saint-Laurent, QC, Canada, H4S 1Z9.
  • 6 AdMare BioInnovations, Saint-Laurent, QC, Canada, H4S 1Z9.
  • 7 Vertex Pharmaceuticals Inc., Boston, MA, 02210, USA.
  • 8 Ra Pharmaceuticals, Inc., Cambridge, MA, 02140, USA.
  • 9 Institute for Research in Immunology and Cancer, and Department of Biochemistry and Molecular Medicine, Université de Montréal, Montréal, QC, Canada, H3C 1J4. michel.bouvier@umontreal.ca.
PMID: 33247181 DOI: 10.1038/s42003-020-01453-8
Abstract

Protease-activated receptor-2 (PAR2) is involved in inflammatory responses and pain, therefore representing a promising therapeutic target for the treatment of immune-mediated inflammatory diseases. However, as for Other GPCRs, PAR2 can activate multiple signaling pathways and those involved in inflammatory responses remain poorly defined. Here, we describe a new selective and potent PAR2 Inhibitor (I-287) that shows functional selectivity by acting as a negative allosteric regulator on Gαq and Gα12/13 activity and their downstream effectors, while having no effect on Gi/o signaling and βarrestin2 engagement. Such selective inhibition of only a subset of the pathways engaged by PAR2 was found to be sufficient to block inflammation in vivo. In addition to unraveling the PAR2 signaling pathways involved in the pro-inflammatory response, our study opens the path toward the development of new functionally selective drugs with reduced liabilities that could arise from blocking all the signaling activities controlled by the receptor.

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