Abstract 1273: Discovery of a potent, selective, and orally bioavailable SOS1 inhibitor, RMC-023, an in vivo tool compound that blocks RAS activation via disruption of the RAS-SOS1 interaction
Authors: Buckl Andreas , Quintana Elsa , Lee Grace J. , Shifrin Nataliya , Zhong Mengqi , Garrenton Lindsay S. , Montgomery David C. , Stahlhut Carlos , Zhao Frances , Whalen Dan M. , Thompson Severin K. , Tambo-ong Arlyn , Gliedt Micah , Knox John E. , Cregg James J. , Aay Naing , Choi Jong , Nguyen Bao , Tripathi Atti , Zhao Ruiping , Saldajeno-Concar Mae , Marquez Abby , Hsieh Daphne , McDowell Laura L. , Koltun Elena S. , Bermingham Alun , Wildes David , Singh Mallika , Wang Zhengping , Hansen Richard , Smith Jan A. , Gill Adrian L. 
Published: July 2021

Abstract
The guanine nucleotide exchange factor (GEF) protein SOS1 activates RAS by promoting its conversion from the GDP-bound RAS(OFF) state to the GTP-bound RAS(ON) state. SOS1 catalyzes or accelerates this nucleotide exchange reaction in response to upstream signals conveyed by a range of growth factor receptors. It acts by promoting the release of tightly bound GDP and thereby facilitating the binding of GTP, which is present at higher intracellular concentrations than GDP, to generate RAS(ON). SOS1 itself is activated by RAS through the binding of RAS(ON) to an allosteric site on the SOS1 protein, which leads to a positive feedback loop between SOS1 and RAS that increases the amplitude and duration of RAS signaling. As a result, there is considerable potential for amplification of RAS signals by SOS1. For this reason, and because SOS1 is a convergent node downstream of RTK signaling, SOS1 represents an attractive therapeutic target in RAS driven cancers. We have developed a collection of novel, proprietary small molecule inhibitors of SOS1. Here we describe the preclinical profile of a potent, selective, and orally bioavailable in vivo tool compound, RM-023, which disrupts the critical interaction between KRAS and SOS1. By preventing formation of the KRAS-SOS1 complex, these inhibitors block reloading of KRAS with GTP, and thereby inhibit RAS pathway signaling and RAS-driven cancer cell growth in vitro. Oral administration of RM-023 produced a dose-dependent suppression of tumor RAS pathway activation in vivo and inhibited tumor growth in preclinical xenograft models of diverse RAS-addicted cancers at well-tolerated doses. Enhanced anti-tumor activity in RAS-addicted cancer models was observed when RM-023 was administered in combination with other RAS pathway inhibitors. We believe SOS1 inhibition represents an attractive companion for combination with RAS-directed inhibitors and may have unique utility in select RAS-addicted tumor types.
Citation Format: Andreas Buckl, Elsa Quintana, Grace J. Lee, Nataliya Shifrin, Mengqi Zhong, Lindsay S. Garrenton, David C. Montgomery, Carlos Stahlhut, Frances Zhao, Dan M. Whalen, Severin K. Thompson, Arlyn Tambo-ong, Micah Gliedt, John E. Knox, James J. Cregg, Naing Aay, Jong Choi, Bao Nguyen, Atti Tripathi, Ruiping Zhao, Mae Saldajeno-Concar, Abby Marquez, Daphne Hsieh, Laura L. McDowell, Elena S. Koltun, Alun Bermingham, David Wildes, Mallika Singh, Zhengping Wang, Richard Hansen, Jan A. Smith, Adrian L. Gill. Discovery of a potent, selective, and orally bioavailable SOS1 inhibitor, RMC-023, an in vivo tool compound that blocks RAS activation via disruption of the RAS-SOS1 interaction [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1273.