Abstract Title
Best in class, potent, SOS1 inhibitors demonstrate single agent activity in preclinical models of KRAS driven tumors
Abstract
Background: KRAS is an oncogene implicated in a wide variety of tumors (~21% of solid tumors harbor KRAS mutations). Interaction of KRAS with its predominant Guanine Exchange Factor (GEF), SOS1, is crucial for activation of KRAS and subsequent KRAS-mediated oncogenic signaling. Pharmacological inhibition of SOS1 is therefore expected to be effective in treating RAS-driven cancers.
Methods: Biochemical potency was confirmed in a SOS1-mediated FRET-based guanine exchange factor (GEF) assay. Selectivity was determined against SOS2 and multiple kinases in the RAS/RAF/MEK and RAS/PI3K/AKT pathways. Anti-proliferative activity was evaluated across WT and mutant KRAS cell lines. Combination studies were performed with MAPK pathway inhibitors and the KRAS G12C inhibitor Sotorasib in 3D anchorage-independent assays. Pharmacodynamic biomarkers (pERK, pAKT) were measured, and PK-PD correlation was established in tumor-bearing mice.
Results: Multiple potent SOS1 inhibitors were identified with IC50 values in the low double-digit nanomolar range. Anti-proliferative IC50 values ranged from 50-200 nM across KRAS-mutant cell lines, with observed synergism in combination therapies. Significant reduction (>50% at 100 nM) in pERK and pAKT was demonstrated in both KRAS mutant and EGFR/PI3K mutant cell lines. Compounds showed excellent ADME properties with significant tissue distribution upon oral dosing. One lead molecule demonstrated ~70% growth inhibition in a KRAS G12C NSCLC xenograft model with no observed adverse effects.
Conclusion: These best-in-class SOS1 inhibitors demonstrate promising single-agent activity in KRAS-driven tumors. IND-enabling studies are currently ongoing for lead compounds, supporting their potential as novel therapeutics for RAS-driven cancers.
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