Identification of Potent Inhibitors Targeting EGFR and HER3 for Effective Treatment of Chemoresistance in Non-Small...

Area of Science:

• Medicinal Chemistry
• Computational Drug Discovery
• Oncology

Background:

• Non-small cell lung cancer (NSCLC) remains a significant health challenge due to its aggressive behavior and high mutation rates.
• EGFR and HER3 are key targets in NSCLC, implicated in therapeutic resistance via pathways like PI3/AKT.
• Developing potent and selective inhibitors for these targets is crucial for overcoming treatment failure.

Purpose of the Study:

• To identify novel small molecules inhibiting Epidermal Growth Factor Receptor (EGFR) and Human Epidermal growth factor Receptor 3 (HER3).
• To evaluate the potential of these inhibitors as therapeutic agents for chemoresistant non-small cell lung cancer.

Main Methods:

• Utilized the BioSolveIT suite for virtual screening and compound library construction (903 compounds).
• Employed pharmacophore modeling and molecular docking using SeeSAR (version 12.1.0) to identify potent binders.
• Conducted in silico preclinical analysis using the SwissADME server for toxicity and pharmacokinetic profiling.

Main Results:

• Identified compounds 4k and 4m as potent inhibitors of EGFR, with binding energies of -7.7 and -6.3 kcal/mol, respectively.
• Compound 7x demonstrated effective inhibition of HER3, exhibiting a binding energy of -5.7 kcal/mol.
• In silico preclinical testing confirmed the non-toxic nature and favorable interactions of compounds 4k, 4m, and 7x with their respective protein targets.

Conclusions:

• Compounds 4k, 4m, and 7x represent promising lead candidates for the development of novel therapies against NSCLC.
• These inhibitors show potential for overcoming chemoresistance by targeting critical pathways mediated by EGFR and HER3.
• The study highlights the efficacy of computational approaches in accelerating the discovery of new anti-cancer agents.