Small molecule Son of Sevenless 1 (SOS1) inhibitors: a review of the patent literature

ABSTRACTABSTRACTIntroduction: Up to 30% of all human cancers are driven by the overactivation of RAS signaling. Son of Sevenless 1 (SOS1) is a central node in RAS signaling pathways and modulation of SOS1-mediated RAS activation represents a unique opportunity for treating RAS-addicted cancers. Several recent publications and patent documents have demonstrated the ability of small molecules to affect the activation of RAS by SOS1 and have shown their potential for the treatment of cancers driven by RAS mutants.Areas covered: Documents focusing on both small-molecule inhibitors and activators of the SOS1:RAS interaction and their potential use as cancer therapeutics are covered. A total of 10 documents from 4 applicants are evaluated with discussion focusing on structural modifications of these compounds as well as relevant preclinical data.Expert opinion: The last decade has seen a significant increase in research and disclosures in the development of small-molecule SOS1 inhibitors. Considering the promising data that have been disclosed, interest in this area of research will likely remain strong for the foreseeable future. With the first SOS1 inhibitor currently in phase I clinical trials, the outcome of these trials will likely influence future development of SOS1 inhibitors for treatment of RAS-driven cancers.KEYWORDS: Son of Sevenless 1 (SOS1)RAScancerdrug discoverymedicinal chemistry AcknowledgmentsThe authors thank Mark Goldsmith, Xiaolin Wang, Jan Smith, Elsa Quintana, Matthew Holderfield, Tamara Kale, and Benjamin Madej for helpful discussion. The authors also thank Benjamin Madej for assistance in producing Figure 1.Article highlightsInhibition of the guanine nucleotide exchange factor SOS1 is a promising approach for the development of small-molecule therapies against cancers addicted to RAS signaling.Interest and activity in the development of SOS1 inhibitors has increased over the last decade, as evidenced by the number of publications and patent applications published to date.The majority of SOS1 inhibitors featured in published patent documents are centered around a bicyclic aromatic core, on which substituents are placed to build in potency in the binding pocket or to sterically disrupt the protein–protein interaction between SOS1 and RAS.With the first SOS1 inhibitor currently in phase I clinical trials, the outcome of these trials will likely influence future drug development of SOS1 inhibitors for the treatment of RAS-driven cancers.This box summarizes key points contained in the article.Declaration of interestSK Thompson, A Buckl and AL Gill are employees of Revolution Medicines. EJ Griffen and AG Dossetter are employees and shareholders of MedChemical Ltd. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.Reviewer disclosuresPeer reviewers on this manuscript have received an honorarium from Expert Opinion on Therapeutic Patents for their review work but have no other relevant financial relationships to disclose.Additional informationFundingThis paper was not funded.