Abstract 4376: Preclinical characterization of SGR-4174, a potent and selective SOS1 inhibitor for the treatment of pan KRAS mutant cancers in combination with KRAS pathway inhibitors

Abstract KRAS is the most frequently mutated oncogene in many tumor types including pancreatic (90%), colorectal (50%) and lung cancers (30%). KRAS mutation typically impairs the conversion of active GTP-bound KRAS to the inactive GDP-bound form, resulting in constitutively active KRAS. SOS1 is a predominant guanine exchange factor (GEF) that binds the inactive GDP-KRAS form and catalyzes conversion to the active GTP-KRAS. SOS1 inhibition has thus been described to be an effective approach for suppressing the KRAS signaling pathway and inhibiting tumor cell proliferation in KRAS mutant-driven cancers. Combination of SOS1 inhibitor with KRAS G12C inhibitor could be an attractive therapeutic approach to enhance the efficacy and overcome the resistance to KRAS G12C inhibitors driven by the reactivation of the RAS pathway observed in the clinic. SGR-4174 is a potent and selective inhibitor of the SOS1-KRAS complex that was rationally designed using Schrödinger’s computational platform. SGR-4174 binds to the catalytic domain of SOS1 (KD = 11 nM), disrupts the SOS1::KRAS interaction (SOS1::KRAS G12C FRET IC50 = 13 nM), and inhibits ERK activation (pERK IC50 = 28-61 nM) and KRAS mutant-driven tumor cell viability (3D CTG IC50 = 42-107 nM). SGR-4174 is effective in broad cancer types harboring KRAS G12C/D/V mutations and KRAS WT/EGFR mutations in drug sensitivity profiling of 49 tumor cell lines. In KRAS G12C tumor xenograft mouse models, SGR-4174 monotherapy demonstrated dose-dependent tumor growth inhibition and a decrease in the tumor PD biomarker pERK. SGR-4174 was examined in combination with KRAS G12C inhibitor sotorasib and MEK inhibitor trametinib in vitro and in vivo. When combined with sotorasib, SGR-4174 demonstrated deeper and more sustained inhibition of the KRAS signaling pathway, stronger suppression of cell proliferation in 3D cell culture, and tumor regression in xenograft models compared to single agent activity. In addition, when combined with trametinib, SGR-4174 suppressed KRAS pathway reactivation by MEK inhibition and led to robust tumor cell death and tumor stasis. Compared to other published SOS1 inhibitors (BI-3406, MRTX0902), SGR-4174 is more potent, and demonstrated similar anti-tumor activity and target engagement at a lower dose both in monotherapy and combination therapy studies in xenograft tumor models. SGR-4174 was well tolerated as monotherapy and in combination with sotorasib or trametinib. SGR-4174 demonstrated favorable PK properties across preclinical species and toxicity profile was well characterized. Our comprehensive preclinical efficacy and safety data support progressing SGR-4174 to clinical development to treat KRAS mutant cancers. Citation Format: Hui Wang, Felicia Gray, Christian Atsriku, Adam M. Levinson, Andrew Placzek, Evelyne M. Houang, Abba E. Leffler, Anatoly Ruvinsky, Leah Frye, Jeremy Greenwood, Mats Svensson, Jeff Bell, Zhijian Liu, Roman Shimanovich, Matt Liu, Shaoxian Sun. Preclinical characterization of SGR-4174, a potent and selective SOS1 inhibitor for the treatment of pan KRAS mutant cancers in combination with KRAS pathway inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4376.