Discovery of Highly Potent and Selective SOS1 Inhibitors for the Treatment of KRAS-Driven Colorectal Cancer.

The guanine nucleotide exchange factor SOS1 has emerged as an attractive therapeutic target for various KRAS-driven tumors. Herein, we employed a structure-based drug design strategy to develop a series of novel quinazoline-derived molecules. This effort yielded highly potent and selective SOS1 inhibitors, 78b and 78d, which displayed high SOS1 binding affinity, potently disrupted the SOS1-KRASG12C interaction, and inhibited nucleotide exchange in WT and multiple KRAS variants. Moreover, both compounds showed submicromolar 3D-antiproliferative activity across a panel of CRC cells, induced G1 phase arrest, and suppressed MAPK and PI3K signaling pathways. Furthermore, 78b and 78d demonstrated favorable safety profiles with no observed adverse effects at levels of 500 and 700 mg/kg, respectively. At doses of 60 mg/kg, they achieved significant tumor growth inhibition (75.1% and 86.2%, respectively) in HCT116 xenograft models without significant toxicity. Collectively, this study identifies potent drug candidates with strong pan-KRAS therapeutic efficacy against colorectal cancer.