Novel Indole Derivatives as SRC/EGFR Inhibitors: Synthesis, Biological Evaluation, and In Silico Analysis
Sureyya Olgen1, Banu Taktak Karaca2,3, Sevde Nur Biltekin Kaleli4
1Department of Pharmaceutical Chemistry, Faculty of Pharmacy, İstinye Üniversity, Vadi Campus, 34396, Sarıyer, İstanbul, Türkiye.
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.
Insights
This study developed novel urea- and pyrimidine-containing compounds as potential dual inhibitors of SRC and EGFR kinases. Compound 20 demonstrated significant activity and is a promising candidate for overcoming cancer therapy resistance.
Area of Science:
- Medicinal Chemistry
- Cancer Biology
- Molecular Pharmacology
Background:
- SRC and EGFR kinases are implicated in tumor aggressiveness and therapy resistance across various cancers.
- Novel therapeutic strategies targeting these kinases are crucial for improving cancer treatment outcomes.
- Osimertinib-like compounds were explored for their potential to inhibit SRC and EGFR, including resistance-conferring mutations.
Purpose of the Study:
- To design and synthesize novel urea- and pyrimidine-containing compounds as potential dual inhibitors of SRC and EGFR kinases.
- To identify compounds that may overcome resistance mechanisms in cancer therapy.
- To evaluate the structure-activity relationships and therapeutic potential of these novel compounds.
Main Methods:
- Synthesis of novel urea- and pyrimidine-containing compounds.
- In vitro enzyme inhibition assays to assess kinase activity.
- Cell culture experiments to evaluate cytotoxicity.
- Molecular docking and molecular dynamics studies to predict interactions with target kinases.
Main Results:
- Compounds 19, 20, and 21 showed significant SRC kinase inhibition (77.75-89.22%).
- Compound 20 exhibited dual inhibition of EGFR (IC50 = 3.91 μM) and SRC (IC50 = 0.00058 μM).
- Compound 20 demonstrated potent cytotoxicity against PC3 prostate cancer cells (IC50 = 6.92 μM) and induced apoptosis via caspase and Bcl-2 family modulation.
Conclusions:
- Compound 20 is a promising dual inhibitor of EGFR and SRC kinases.
- In silico analyses support the therapeutic potential of compound 20.
- Compound 20 warrants further investigation for cancer treatment applications.
