Abstract 4374: Discovery of a highly potent and efficacious SOS1 inhibitor targeting KRAS-driven cancers

Abstract SOS1 is a crucial protein that activates RAS by promoting its conversion from the inactive GDP-bound state to the active GTP-bound state, triggered by growth factor receptor signals. This process is further enhanced by a feedback mechanism between SOS1 and RAS, increasing the strength and duration of RAS signaling, making SOS1 a significant therapeutic target in the RAS-MAPK pathway. Genetic alterations in the RAS-MAPK pathway are frequently observed across a spectrum of cancer types. While therapies targeting KRAS G12C mutations has been approved for certain types of lung cancers, there remains a need for treatments addressing other mutations (e.g. KRAS G12D, G12V etc.). Inhibiting SOS1 has shown potential in reducing proliferation of cancer cells dependent on KRAS signaling. Here, we report the discovery of a highly potent and efficacious SOS1 inhibitor HW071021. It demonstrates an IC50 of 8.5 nM in SOS1 binding assay and modulates ERK1/2 phosphorylation (pERK) in DLD-1 cell assay. Oral administration of HW071021 as a monotherapy in mouse MIA PaCa-2 xenograft models harboring KRAS G12C mutations results in significant tumor growth inhibition (TGI:∼78%). Additionally, HW071021 combination with the EGFRi Osimertinib demonstrated much greater antitumor activity than Osimertinib monotherapy (TGI: 97% vs 33%) in mouse NCI-H1975 (EGFR L858R/T90M) xenograft model. HW071021 has excellent ADME and physical properties with low risks of hERG-related cardiotoxicity and drug-drug interactions . These data support the clinical utility of HW071021 as a single agent or combination partner of Osimertinib for the treatment of human Kras-driven cancers. IND application in China has been approved in September. Citation Format: Yang Li, Yang Zang, Wenbing Hu, Yuan Zhou, Lifei Liu, Xuejun Zhang, Shaohua Chang. Discovery of a highly potent and efficacious SOS1 inhibitor targeting KRAS-driven cancers [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 4374.