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

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.

Discovery of novel SOS1 inhibitors using machine learning

“…Another compound, MRTX0902, with a pyridopyridazine core, has just entered clinical trials (NCT05578092), which are designed to elucidate the effectiveness of MRTX0902, either alone or in combination with MRTX849 (adagrasib), in treating solid tumours malignancies among patients harbouring KRAS G12C mutations. 12 Similar research has been published by Revolution Medical 13 and He et al 14,15 for the SOS1 inhibitors: RMC-0331 with a pyrrolo [3,4-d]pyrimidine scaffold and the tetracyclicquinazoline (37 and 13c) with superior pharmacokinetic properties, respectively (see Fig. 2).…”

Discovery of Five SOS2 Fragment Hits with Binding Modes Determined by SOS2 X-Ray Cocrystallography

“…Several reports have detailed the discovery of SOS1:KRAS PPI activators ( 1 ) and SOS1:KRAS PPI inhibitors ( 2– 6 ), − ,, as shown in Figure . Compounds 1 – 6 bind to SOS1 in the binding site known as “site-A” adjacent to the Switch II region of KRAS.…”

Lead Identification of Novel Naphthyridine Derivatives as Potent SOS1 Inhibitors

“…Subsequently another quinazoline compound BI-3406 ( 2 ) with an improved activity compared with BAY-293 was disclosed by scientists from Boehringer Ingelheim through a high-throughput screening (HTS) campaign and structure-based drug design and optimization efforts . The discovery of compounds 1 and 2 demonstrates the feasibility of SOS1 binder to interrupt KRAS-SOS1 PPIs and initiate a new paradigm to design novel SOS1 inhibitors, , which is illustrated by RMC-0331 ( 3 ), MRTX-0902 ( 4 ), 5 , and 6 . Differentiating from the classical quinazoline scaffold, MRTX-0902 ( 4 ) with a phthalazine core was reported by Mirati Therapeutics and now is in Phase I/II study with indications for solid tumors (ClinicalTrials.gov Identifier: NCT05578092).…”