Title:Synthesis and Anticancer Activity of Novel Indole Derivatives as Dual
EGFR/SRC Kinase Inhibitors
Volume: 31
Issue: 24
关键词:
抗癌活性，激酶抑制剂，EGFR, SRC，对接，抑制，凋亡。
摘要:
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.
