Design, Synthesis, and Biological Evaluation of Novel 1 H‑Imidazo[4,5-g]quinazoline-Based SOS1::KRASG12C Inhibitors in Colorectal Cancer Cells
- ACS Med Chem Lett. 2026 Feb 16;17(3):711-720. doi: 10.1021/acsmedchemlett.5c00754.
- 1. College & Hospital of Stomatology, Anhui Medical University, Key Lab. of Oral Diseases Research of Anhui Province, Hefei 230032, China.
- 2. School of Pharmacy, Anhui Medical University, Hefei 230032, China.
- 3. School of Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, PR China.
- 4. Department of Pharmacy, The Third Affiliated Hospital of Anhui Medical University, Hefei First People's Hospital, Hefei 230032, China.
- 5. AnHui College of Traditional Chinese Medicine. 18 Wuxia West Road, Yijiang District, Wuhu 241000, China.
Colorectal Cancer remains a leading cause of cancer-related mortality. Although KRASG12C 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::KRASG12C 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.