Inhibition of Oncogenic Kinases: An In Vitro Validated Computational Approach Identified Potential Multi-Target...

Area of Science:

• Computational chemistry and drug discovery
• Oncology and molecular biology

Background:

• Tumorigenesis involves genetic changes leading to cell transformation and malignancy.
• Oncogenic kinases, including receptor tyrosine kinases (RTKs) and serine/threonine kinases (STKs), are key drivers of cancer progression.
• Targeting these kinases offers a promising strategy for anti-cancer drug development.

Purpose of the Study:

• To identify potential multi-target inhibitors for oncogenic RTKs and STKs.
• To validate lead compounds through in vitro cytotoxicity assays.
• To explore the stability and binding interactions of kinase-compound complexes using molecular dynamics simulations.

Main Methods:

• Chemoinformatics and structure-based virtual screening of approximately 739,000 compounds against 16 kinase structures.
• Filtering of top hits for favorable pharmacokinetic properties.
• In vitro validation of selected compounds on cancerous and non-cancerous cell lines, including cytotoxicity assays and molecular dynamics simulations.

Main Results:

• Identification of 12 and 9 potential inhibitors for RTKs and STKs, respectively.
• Compound F34 exhibited significant inhibitory activity across HeLa, HepG2, and Vero cell lines, with IC50 values ranging from 130.52 μM to 175.48 μM.
• Molecular dynamics simulations supported the stability of kinase-compound complexes, and docking studies suggested multi-target inhibition potential for F34.

Conclusions:

• The study successfully identified novel multi-target scaffolds for RTKs and STKs.
• Compound F34 demonstrates promising anti-cancer potential, warranting further investigation for drug development.
• These findings support the development of kinase-specific anti-cancer drugs and combinatorial therapies.