Giubilaro, JennaSchuetz, Doris A.Stepniewski, Tomasz Maciej, 1988-Namkung, YoonKhoury, EtienneLara Márquez, MónicaCampbell, ShirleyBeautrait, AlexandreArmando, SylvainRadresa, OlivierDuchaine, JeanLamarche Vane, NathalieClaing, AudreySelent, JanaBouvier, MichelMarinier, AnneLaporte, Stéphane A.2021-10-062021-10-062021Giubilaro J, Schuetz DA, Stepniewski TM, Namkung Y, Khoury E, Lara-Márquez M, Campbell S, Beautrait A, Armando S, Radresa O, Duchaine J, Lamarche-Vane N, Claing A, Selent J, Bouvier M, Marinier A, Laporte SA. Discovery of a dual Ras and ARF6 inhibitor from a GPCR endocytosis screen. Nat Commun. 2021;12(1):4688. DOI: 10.1038/s41467-021-24968-y2041-1723http://hdl.handle.net/10230/48573Internalization 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.application/pdfeng© The Author(s) 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.info:eu-repo/semantics/articlehttp://dx.doi.org/10.1038/s41467-021-24968-yHormone receptorsScreeninginfo:eu-repo/semantics/openAccess