Design, Synthesis, and Biological Evaluation of Novel 1 H‑Imidazo[4,5-g]quinazoline-Based SOS1::KRASG12C Inhibitors in Colorectal Cancer Cells

Colorectal Cancer remains a leading cause of cancer-related mortality. Although KRAS^G12C inhibitors have been approved for the treatment of multiple cancers, their clinical efficacy is often limited by KRAS reactivation. SOS1, a key guanine nucleotide exchange factor involved in KRAS activation and implicated in various malignancies, including colorectal and oral cancers, represents an attractive therapeutic target. In this study, fragment-based virtual screening targeting the Asn879 pocket of SOS1 was performed using the DrugBank database and an in-house chemical library, followed by structure-based optimization and structure-activity relationship analysis. Twenty derivatives were synthesized, among which compound 20, featuring a 6-methyl-1H-imidazo-[4,5-g]-quinazoline scaffold, exhibited the most potent inhibition of the SOS1::KRAS^G12C interaction (IC₅₀ = 4.11 nM). Compound 20 also demonstrated significant antiproliferative activity against DLD-1 CRC cells by inducing Apoptosis and G0/G1 cell-cycle arrest. These results identify compound 20 as a promising lead for SOS1-targeted therapy.

Cancers; Colorectal; Oral; SOS1; SOS1::KRASG12C.