LAUSR

KRAS occurs Mutation in approximately one in seven of all human cancers, making it the most frequently mutated oncogene. The activation of KRAS protein is regulated via switching the cycle between the active form, guanosine- 5′-triphosphate (GTP)-bound state and the inactive form, guanosine-5′-diphosphate (GDP)-bound form. Guanine nucleotide-exchange factors (GEF), including SOS1/2 play a key role in catalyzing the transformation of KRAS from GDP to GTP form. In tumors with dysregulation of the MAPK signal axis, inhibition of SOS1/2 leads to abrogation of the Kras-mediated activation of downstream signals. However, double depletion of SOS1/2 is embryo lethal, and selective inhibition of SOS1 provides a more balanced therapy for Kras mutant tumors. Here we reported SCR-8388 as a highly potent and SOS1- specific inhibitor that effectively inhibited multiple Kras-mutant oncoproteins. SCR-8388 was potently bound to SOS1 and blocked the interaction of KRASG12D-GDP or KRASG12C-GDP with IC50 at single-digit nanomolar level. In contrast, SCR-8388 had no effect on the interaction of KRASG12C-GDP and SOS2. In H358 (KRASG12C) cells, SCR-8388 strongly inhibited the phosphorylation of ERK1/2 with an IC50 of 20 nM. The anti-proliferation activities of SCR-8388 on Kras mutant tumor cell lines were determined using the anchorage-independent three-dimensional (3-D) growth assay. The results showed that SCR-8388 strongly inhibited cell growth in five Kras-mutant cell lines which represent the different Kras mutation genotypes, including G12D, G12C, G12S and G13D mutants, the IC50s ranged from 17 to 120 nM, suggesting the broad activities of SOS1 inhibitor against pan-Kras mutation. In contrast, SCR-8388 (at 1 µM) showed no growth inhibition on two Kras non-addicted cancer cell lines, NCI-H520 and A375. Additionally, SCR-8388 demonstrated enhanced antiproliferation activity in a SOS2 knockout cell line (H358SOS2-/-) in comparison with the parental cells, indicating the high selectivity of SCR-8388 over SOS2. SCR-8388 displayed favorable PK properties, and higher tissue exposure, making SCR-8388 achieve effective tumor growth inhibition. In a subcutaneous MIA PaCa-2 xenograft model, oral administration of SCR-8388 resulted in superior tumor growth control in comparison with the clinical reference. Moreover, the robust anti-tumor efficacy was further observed in another KRASG13D-mutated DLD-1 xenograft model. Furthermore, SCR-8388 exhibited synergistic anti-tumor activity in combination with several MAPK pathway inhibitors, including KRASG12C, MEK, and ERK inhibitors as excepted. Notably, SCR-8388 demonstrated synergistic effects with the anti-EGFR antibody (cetuximab) both in Kras-mutant and WT cell lines in vitro and in vivo. In summary, SCR-8388 is a highly potent and selective SOS1 inhibitor, and effectively inhibits Kras-mutant tumors as mono- or combo therapeutics. Citation Format: Feng Zhou, Guimei Yang, Feng Tang Tang, Yan Zhang, Shengwei Yang, Wenqing Yang, Liting Xue, Ping Chen, Renhong Tang. SCR-8388, a potent and selective SOS1::KRAS inhibitor, is effective in KRAS-addicted cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1724.