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Design, Synthesis, and Biological Evaluation of Novel 1H‑Imidazo[4,5-g]quinazoline-Based SOS1::KRASG12C Inhibitors in
Xu Huang1,2, Jingkun Huang3, Qianqian Hong4
1College & Hospital of Stomatology, Anhui Medical University, Key Lab. of Oral Diseases Research of Anhui Province, Hefei 230032, China.
Abstract:
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.
Insights
Researchers developed a novel compound, compound 20, that effectively inhibits SOS1::KRASG12C interactions. This discovery offers a promising new therapeutic strategy for colorectal cancer treatment by targeting KRAS reactivation.
Area of Science:
- Oncology
- Medicinal Chemistry
- Molecular Biology
Background:
- Colorectal cancer (CRC) is a major cause of cancer mortality.
- KRASG12C inhibitors show promise but face limitations due to KRAS reactivation.
- SOS1 is a key regulator of KRAS activation and a potential therapeutic target in cancers like CRC.
Purpose of the Study:
- To identify novel inhibitors of SOS1 that can block SOS1::KRASG12C interactions.
- To develop and optimize small molecules targeting SOS1 for potential CRC therapy.
Main Methods:
- Fragment-based virtual screening of SOS1's Asn879 pocket using DrugBank and an in-house library.
- Structure-based optimization and structure-activity relationship (SAR) analysis.
- Synthesis and in vitro evaluation of twenty novel SOS1 inhibitor derivatives.
Main Results:
- Compound 20, a 6-methyl-1H-imidazo-[4,5-g]-quinazoline derivative, potently inhibited SOS1::KRASG12C interaction (IC50 = 4.11 nM).
- Compound 20 exhibited significant antiproliferative effects on DLD-1 CRC cells.
- The compound induced apoptosis and G0/G1 cell-cycle arrest in CRC cells.
Conclusions:
- Compound 20 represents a promising lead molecule for SOS1-targeted therapy in colorectal cancer.
- Inhibition of SOS1 is a viable strategy to overcome KRAS reactivation in CRC.
- Further development of compound 20 could lead to novel treatments for KRAS-driven cancers.
