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

Tumorigenesis in humans is a multistep progression that imitates genetic changes leading to cell transformation and malignancy. Oncogenic kinases play a central role in cancer progression, rendering them putative targets for the design of anti-cancer drugs. The presented work aims to identify the potential multi-target inhibitors of oncogenic receptor tyrosine kinases (RTKs) and serine/threonine kinases (STKs). For this, chemoinformatics and structure-based virtual screening approaches were combined with an in vitro validation of lead hits on both cancerous and non-cancerous cell lines. A total of 16 different kinase structures were screened against ~739,000 prefiltered compounds using diversity selection, after which the top hits were filtered for promising pharmacokinetic properties. This led to the identification of 12 and 9 compounds against RTKs and STKs, respectively. Molecular dynamics (MD) simulations were carried out to better comprehend the stability of the predicted hit kinase-compound complexes. Two top-ranked compounds against each kinase class were tested in vitro for cytotoxicity, with compound F34 showing the most promising inhibitory activity in HeLa, HepG2, and Vero cell lines with IC values of 145.46 μM, 175.48 μM, and 130.52 μM, respectively. Additional docking of F34 against various RTKs was carried out to support potential multi-target inhibition. Together with reliable MD simulations, these results suggest the promising potential of identified multi-target STK and RTK scaffolds for further kinase-specific anti-cancer drug development toward combinatorial therapies.