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

Jenna Giubilaro, Doris A. Schuetz, Tomasz M. Stepniewski, Yoon Namkung, Etienne Khoury, Mónica Lara-Márquez, Shirley Campbell, Alexandre Beautrait, Sylvain Armando, Olivier Radresa, Jean Duchaine, Nathalie Lamarche-Vane, Audrey Claing, Jana Selent, Michel Bouvier, Anne Marinier and Stéphane A. Laporte ()
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Jenna Giubilaro: McGill University
Doris A. Schuetz: Université de Montréal
Tomasz M. Stepniewski: Fabra University (UPF)-Hospital del Mar Medical Research Institute (IMIM)
Yoon Namkung: Research Institute of the McGill University Health Center (RI-MUHC)
Etienne Khoury: McGill University
Mónica Lara-Márquez: Research Institute of the McGill University Health Center (RI-MUHC)
Shirley Campbell: Université de Montréal
Alexandre Beautrait: Université de Montréal
Sylvain Armando: McGill University
Olivier Radresa: McGill University
Jean Duchaine: Université de Montréal
Nathalie Lamarche-Vane: Research Institute of the McGill University Health Center (RI-MUHC)
Audrey Claing: Université de Montréal
Jana Selent: Fabra University (UPF)-Hospital del Mar Medical Research Institute (IMIM)
Michel Bouvier: Université de Montréal
Anne Marinier: Université de Montréal
Stéphane A. Laporte: McGill University

Nature Communications, 2021, vol. 12, issue 1, 1-16

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-24968-y

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