2. Academic Validation
  3. Discovery of a dual Ras and ARF6 inhibitor from a GPCR endocytosis screen

Discovery of a dual Ras and ARF6 inhibitor from a GPCR endocytosis screen

  • Nat Commun. 2021 Aug 3;12(1):4688. doi: 10.1038/s41467-021-24968-y.
Jenna Giubilaro 1 2,  Doris A Schuetz 3,  Tomasz M Stepniewski 4 5,  Yoon Namkung 2 6,  Etienne Khoury 6,  Mónica Lara-Márquez 2 7,  Shirley Campbell 8,  Alexandre Beautrait 3 9,  Sylvain Armando 6,  Olivier Radresa 6,  Jean Duchaine 3,  Nathalie Lamarche-Vane 2 7,  Audrey Claing 8,  Jana Selent 4,  Michel Bouvier 3 10,  Anne Marinier 3,  Stéphane A Laporte 11 12 13
Affiliations

Affiliations

  • 1 Department of Pharmacology and Therapeutics, McGill University, Montréal, QC, Canada.
  • 2 Research Institute of the McGill University Health Center (RI-MUHC), Montreal, QC, Canada.
  • 3 Institute for Research in Immunology and Cancer (IRIC), Université de Montréal, Montréal, QC, Canada.
  • 4 Research Programme on Biomedical Informatics (GRIB), Department of Experimental and Health Sciences of Pompeu, Fabra University (UPF)-Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain.
  • 5 InterAx Biotech AG, Villigen, Switzerland.
  • 6 Department of Medicine, Research Institute of the McGill University Health Center (RI-MUHC), McGill University, Montréal, QC, Canada.
  • 7 Department of Anatomy and Cell Biology, McGill University, Montréal, QC, Canada.
  • 8 Department of Pharmacology and Physiology, Université de Montréal, Montréal, QC, Canada.
  • 9 Schrödinger, Inc., New York, NY, United States.
  • 10 Department of Biochemistry and Molecular Medicine, Université de Montréal, Montréal, QC, Canada.
  • 11 Department of Pharmacology and Therapeutics, McGill University, Montréal, QC, Canada. [email protected].
  • 12 Research Institute of the McGill University Health Center (RI-MUHC), Montreal, QC, Canada. [email protected].
  • 13 Department of Medicine, Research Institute of the McGill University Health Center (RI-MUHC), McGill University, Montréal, QC, Canada. [email protected].
PMID: 34344896 DOI: 10.1038/s41467-021-24968-y
Abstract

Internalization and intracellular trafficking of G protein-coupled receptors (GPCRs) play pivotal roles in cell responsiveness. Dysregulation in receptor trafficking can lead to aberrant signaling and cell behavior. Here, using an endosomal BRET-based assay in a high-throughput screen with the prototypical GPCR angiotensin II type 1 receptor (AT1R), we sought to identify receptor trafficking inhibitors from a library of ~115,000 small molecules. We identified a novel dual Ras and ARF6 inhibitor, which we named Rasarfin, that blocks agonist-mediated internalization of AT1R and other GPCRs. Rasarfin also potently inhibits agonist-induced ERK1/2 signaling by GPCRs, and MAPK and Akt signaling by EGFR, as well as prevents Cancer cell proliferation. In silico modeling and in vitro studies reveal a unique binding modality of Rasarfin within the SOS-binding domain of Ras. Our findings unveil a class of dual small G protein inhibitors for receptor trafficking and signaling, useful for the inhibition of oncogenic cellular responses.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-139950
    99.57%, Ras/ARF6 Inhibitor
    Ras