Abstract 4373: Discovery and characterization of BAY 3498264: a small molecule inhibitor targeting the RAS-SOS1 interaction
Authors: Nils Guthof, Hongyu Xue, Isabel Jerchel-Furau, Christoph Hethey, Jan-Erik Busse, Karsten Denner, Zebin Wang, Volker Schulze, Sangeeta Jethwa, Shinghu Cheung
Journal: Cancer Research (2025)

Abstract RAS proteins are GTPases cycling between the active GTP-bound on-state and inactive GDP-bound off-state. KRAS is among the most frequently mutated genes in cancers including non-small cell lung cancer, colorectal cancer and pancreatic cancer. Recent regulatory approvals of KRAS G12C selective inhibitors (KRAS G12Cis) including sotorasib and adagrasib have offered clinical advances to patients with cancer harboring the KRAS G12C mutation. However, monotherapy with these inhibitors showed modest response rate with median duration of response of less than one year for both. It has been shown preclinically that there is a feedback activation of the MAPK pathway when the pathway is being suppressed. This on-treatment feedback reactivation of the MAPK pathway is hypothesized to play an important role in limiting the clinical efficacy of KRAS G12Cis. Therefore, rational combination approaches are needed to address the feedback reactivation. The MAPK pathway is intricately regulated by negative feedback mechanisms, including ERK-mediated inactivation of SOS1. As a guanine nucleotide exchange factor, SOS1 interacts with RAS to promote the exchange of GDP for GTP, thus facilitating RAS activation. Inhibiting SOS1, a crucial node within the MAPK pathway negative feedback loop, could block the feedback reactivation of MAPK pathway via RAS, akin to the effect seen with SHP2 inhibitors as reported, yet potentially with better tolerability. Indeed, our preclinical data have demonstrated that inhibiting SOS1 enhances the duration and depth of response of KRAS G12Cis, suggesting that SOS1 inhibitors could improve the therapeutic outcomes of KRAS G12Cis in patients. Here, we report on the preclinical characterization of BAY 3498264, a potent and selective small molecule oral inhibitor of the SOS1 and RAS interaction. In KRAS G12C mutant cells, BAY 3498264 inhibits the rebound of phospho-ERK induced by sotorasib, achieving a more prolonged ERK phosphorylation inhibition when combined. Additionally, in in vitro proliferation assays, combining BAY 3498264 with various MAPK pathway inhibitors demonstrates marked combination effect as compared to single agent MAPK inhibition. The combination of BAY 3498264 with sotorasib in KRAS G12C mutant CDX and PDX models in vivo is well tolerated and exhibits combination benefit, enhancing both the depth and duration of response over sotorasib alone. Furthermore, we have assessed combination of BAY 3498264 with additional MAPK pathway directed therapies in vivo and have demonstrated combination effect with multiple molecules in addition to KRAS G12Cis. Our findings support the clinical exploration of BAY 3498264 in combination with KRAS G12Cis, and other therapies targeting the MAPK pathway, potentially offering a more durable blockage of the pathway and greater benefit for patients. BAY 3498264 is now in the early stages of a novel phase I study (NCT06659341). Citation Format: Nils Guthof, Hongyu Xue, Isabel Jerchel-Furau, Christoph Hethey, Jan-Erik Busse, Karsten Denner, Zebin Wang, Volker Schulze, Sangeeta Jethwa, Shinghu Cheung. Discovery and characterization of BAY 3498264: a small molecule inhibitor targeting the RAS-SOS1 interaction [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 4373.