Peter Ettmayer

Abstract KRAS is the most frequently mutated driver of pancreatic, colorectal, and non–small cell lung cancers. Direct KRAS blockade has proved challenging, and inhibition of a key downstream effector pathway, the RAF–MEK–ERK cascade, has shown limited success because of activation of feedback networks that keep the pathway in check. We hypothesized that inhibiting SOS1, a KRAS activator and important feedback node, represents an effective approach to treat KRAS-driven cancers. We report the discovery of a highly potent, selective, and orally bioavailable small-molecule SOS1 inhibitor, BI-3406, that binds to the catalytic domain of SOS1, thereby preventing the interaction with KRAS. BI-3406 reduces formation of GTP-loaded RAS and limits cellular proliferation of a broad range of KRAS-driven cancers. Importantly, BI-3406 attenuates feedback reactivation induced by MEK inhibitors and thereby enhances sensitivity of KRAS-dependent cancers to MEK inhibition. Combined SOS1 and MEK inhibition represents a novel and effective therapeutic concept to address KRAS-driven tumors. Significance: To date, there are no effective targeted pan-KRAS therapies. In-depth characterization of BI-3406 activity and identification of MEK inhibitors as effective combination partners provide an attractive therapeutic concept for the majority of KRAS-mutant cancers, including those fueled by the most prevalent mutant KRAS oncoproteins, G12D, G12V, G12C, and G13D. See related commentary by Zhao et al., p. 17. This article is highlighted in the In This Issue feature, p. 1

ADVERTISEMENT RETURN TO ISSUEPerspectiveNEXTLessons Learned from Marketed and Investigational ProdrugsPeter Ettmayer, Gordon L. Amidon, Bernd Clement, and Bernard TestaView Author Information Novartis Institute for BioMedical Research, Brunnerstrasse 59, A-1235 Vienna, Austria, College of Pharmacy, The University of Michigan, Ann Arbor, Michigan 48109-1065, Pharmaceutical Institute, University of Kiel, D-24118 Kiel, Germany, and Department of Pharmacy, University Hospital Centre (CHUV), CH-1011 Lausanne, Switzerland Cite this: J. Med. Chem. 2004, 47, 10, 2393–2404Publication Date (Web):April 13, 2004Publication History Received7 August 2003Published online13 April 2004Published inissue 1 May 2004https://doi.org/10.1021/jm0303812Copyright © 2004 American Chemical SocietyRIGHTS & PERMISSIONSArticle Views6980Altmetric-Citations282LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit Read OnlinePDF (231 KB) Get e-AlertsSUBJECTS:Cells,Metabolism,Peptides and proteins,Pharmaceuticals,Targeting Get e-Alerts