Synthesis and Anticancer Activity of Novel Indole Derivatives as Dual EGFR/SRC Kinase Inhibitors
Sureyya Olgen1, Sevde Nur Biltekin Kaleli2, Banu Taktak Karaca3,4
1Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Biruni University, 34010, Zeytinburnu, Istanbul, Turkey.
Background:
Recent studies showed that the cooperation between c-SRC and EGFR is responsible for more aggressive phenotype in diverse tumors, including glioblastomas and carcinomas of the colon, breast, and lung. Studies show that combination of SRC and EGFR inhibitors can induce apoptosis and delay the acquired resistance to chemotherapy. Therefore, such combination may lead to a new therapeutic strategy for the treatment of EGFR-mutant lung cancer. Osimertinib was developed as a third-generation EGFR-TKI to combat the toxicity of EGFR mutant inhibitors. Due to the resistance and adverse reaction of osimertinib and other kinase inhibitors, 12 novel compounds structurally similar to osimertinib were designed and synthesized.
Methods:
Compounds were synthesized by developing novel original synthesis methods and receptor interactions were evaluated through a molecular docking study. To evaluate their inhibitory activities against EGFR and SRC kinase, in vitro enzyme assays were used. Anticancer potencies were determined using lung, breast, prostate (A549, MCF6, PC3) cancer cell lines. Compounds were also tested against normal (HEK293) cell line to evaluate their cyctotoxic effects.
Results:
Although, none of compounds showed stronger inhibition compared to osimertinib in the EGFR enzyme inhibition studies, compound 16 showed the highest efficacy with an IC50 of 1.026 μM. It also presented potent activity against SRC kinase with an IC50 of 0.002 μM. Among the tested compounds, the urea containing derivatives 6-11 exhibited a strong inhibition profile (80.12-89.68%) against SRC kinase in comparison to the reference compound dasatinib (93.26%). Most of the compounds caused more than 50% of cell death in breast, lung and prostate cancer cell lines and weak toxicity for normal cells in comparison to reference compounds osimertinib, dasatinib and cisplatin. Compound 16 showed strong cytotoxicity on lung and prostate cancer cells. Treatment of prostate cancer cell lines with the most active compound, 16, significantly increased the caspase-3 (8-fold), caspase-8 (6-fold) and Bax (5.7-fold) levels and decreased the Bcl-2 level (2.3-fold) compared to the control group. These findings revealed that the compound 16 strongly induces apoptosis in the prostate cancer cell lines.
Conclusion:
Overall kinase inhibition, cytotoxicity and apoptosis assays presented that compound 16 has dual inhibitory activity against SRC and EGFR kinases while maintaining low toxicity against normal cells. Other compounds also showed considerable activity profiles in kinase and cell culture assays.
Insights
Novel compounds targeting SRC and EGFR kinases were synthesized to combat cancer resistance. Compound 16 demonstrated dual inhibitory activity against SRC and EGFR, showing potent anticancer effects with low toxicity to normal cells, offering a promising therapeutic strategy.
Area of Science:
- Medicinal Chemistry
- Oncology
- Molecular Biology
Background:
- Cooperation between c-SRC and EGFR drives aggressive phenotypes in various cancers.
- Combination therapy with SRC and EGFR inhibitors shows potential in inducing apoptosis and overcoming chemotherapy resistance.
- Osimertinib, a third-generation EGFR-TKI, faces challenges with resistance and adverse reactions, necessitating novel therapeutic agents.
Purpose of the Study:
- Design and synthesize novel compounds structurally similar to osimertinib.
- Evaluate the inhibitory activities of these compounds against EGFR and SRC kinases.
- Assess their anticancer potency and cytotoxicity in various cancer cell lines.
Main Methods:
- Novel synthesis methods were employed for compound preparation.
- Molecular docking studies assessed receptor interactions.
- In vitro enzyme assays evaluated inhibitory activities against EGFR and SRC kinases.
- Anticancer potency was determined using A549, MCF6, and PC3 cancer cell lines, with HEK293 cells used for cytotoxicity assessment.
Main Results:
- Compound 16 exhibited the highest efficacy against EGFR (IC50 = 1.026 μM) and potent activity against SRC kinase (IC50 = 0.002 μM).
- Urea-containing derivatives (6-11) showed strong SRC kinase inhibition (80.12-89.68%).
- Most compounds demonstrated significant cancer cell death (>50%) with low toxicity to normal cells.
- Compound 16 induced apoptosis in prostate cancer cells by increasing caspase-3, caspase-8, and Bax levels, and decreasing Bcl-2 levels.
Conclusions:
- Compound 16 possesses dual inhibitory activity against SRC and EGFR kinases with favorable safety profiles.
- The synthesized compounds show considerable potential for developing new anticancer therapies.
- Further research into these compounds could lead to improved treatment strategies for EGFR-mutant lung cancer and other malignancies.
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