Targeting EGFR tyrosine kinase: Synthesis, in vitro antitumor evaluation, and molecular modeling studies of...

Area of Science:

• Medicinal Chemistry
• Oncology
• Molecular Biology

Background:

• Cancer remains a leading cause of mortality worldwide, necessitating the development of novel therapeutic agents.
• Targeting key signaling pathways, such as the Epidermal Growth Factor Receptor (EGFR), is a crucial strategy in cancer treatment.
• Benzothiazole scaffolds have demonstrated diverse biological activities, including anticancer properties.

Purpose of the Study:

• To synthesize and evaluate novel benzothiazole-based derivatives for their in vitro antitumor activity.
• To investigate the EGFR inhibitory potential of the most active compounds.
• To elucidate the binding interactions of potent compounds with the EGFR active site using molecular modeling.

Main Methods:

• Synthesis of novel benzothiazole derivatives.
• In vitro antitumor assays against HepG2, HCT-116, MCF-7, PC-3, and HeLa cancer cell lines.
• Epidermal Growth Factor Receptor (EGFR) inhibitory activity assay.
• Molecular docking and surface mapping studies into the EGFR active site.

Main Results:

• Several synthesized benzothiazole derivatives exhibited significant in vitro antitumor activity, with IC50 values comparable to lapatinib.
• Compounds 39 and 40 demonstrated potent EGFR inhibition, with IC50 values of 24.58 nM and 30.42 nM, respectively.
• Molecular modeling studies confirmed the strong binding affinity of compounds 39 and 40 to the EGFR active site, particularly highlighting hydrazone derivatives.

Conclusions:

• The novel benzothiazole derivatives, especially compounds 39 and 40, show significant potential as antitumor agents.
• These compounds effectively inhibit EGFR kinase, suggesting a mechanism for their anticancer activity.
• The synthesized hydrazone derivatives are promising candidates for developing targeted antitumor therapies via EGFR kinase inhibition.