Novel Indole Derivatives as SRC/EGFR Inhibitors: Synthesis, Biological Evaluation, and In Silico Analysis

English (OpenAlex)

Introduction: Recent studies have reported a correlation between SRC and EGFR as key factors contributing to tumor aggressiveness in cancers, such as glioblastoma, colon, breast, and lung cancers. Resistance to therapy remains a major obstacle in cancer treatment. Therefore, the discovery of novel compounds with inhibitory potential is crucial. In this study, urea- and pyrimidine-containing compounds structurally similar to osimertinib were designed as potential inhibitors of both SRC and EGFR kinases, with the aim of identifying compounds that may also overcome resistance conferred by mutations. Methods: The compounds were synthesized through the development of new synthetic routes. Their structure-activity relationships (SAR) were evaluated using in vitro enzyme inhibition assays, cell culture experiments, molecular docking, and molecular dynamics studies. Results: Compounds 19, 20, and 21, which bear substitutions at the third position of the indole ring, inhibited SRC kinase with 77.75–89.22% activity. These compounds also demonstrated notable cytotoxicity against the PC3 cell line, with IC50 values of 7.89, 6.92, and 9.85 μM, respectively, comparable to reference compounds cisplatin (IC50 = 5.16 μM) and dasatinib (IC50 = 0.9 μM). Notably, compound 20 was active against both EGFR and SRC kinases, with IC50 values of 3.91 μM and 0.00058 μM, respectively. Compound 20 also exhibited the strongest cytotoxic effect on prostate cancer cells (IC50 = 6.92 μM). Further analyses indicated that compound 20 induced apoptosis in cancer cells by increasing the levels of caspase-3, caspase-8, and Bax, while reducing Bcl-2 expression. Molecular docking and dynamics studies revealed strong interactions of compound 20 with the target receptors. Discussion: Docking and biological activity studies indicated that compound 20 (1-(2- Fluoro-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidine-2-yl)amino)phenyl)-3- phenylurea) is a promising dual inhibitor of both EGFR and SRC kinases. In silico analyses further support the potential therapeutic efficacy of compound 20. Conclusion: Overall, compound 20 emerged as the most promising candidate from this study, warranting further investigation for its therapeutic potential.