Design and Computational Assessment of Hybrid Molecules for Simultaneous Tyrosine Kinase and PI3K Inhibition in Cancer

The dysregulation of tyrosine kinases (TKs) and phosphoinositide 3-kinases (PI3Ks) plays a pivotal role in oncogenesis by promoting aberrant cell proliferation, survival, and resistance to apoptosis. Despite the clinical efficacy of monotherapies targeting either TKs or PI3Ks, compensatory feedback mechanisms and signaling cross-talk often limit their therapeutic effectiveness. In this study, a rational structure-based drug design approach was employed to develop novel hybrid molecules capable of dual inhibition of both TKs and PI3Ks. Pharmacophoric elements from established inhibitors were strategically integrated to yield compounds with enhanced therapeutic potential. Molecular docking studies against key cancer-related kinases—EGFR, BCR-ABL, and PI3Kα—revealed that compounds S4 and S5 exhibited superior binding affinities and a robust network of non-covalent interactions within the active sites, surpassing the performance of standard inhibitors. ADMET analyses conducted via SwissADME, pkCSM, and ProTox-II demonstrated that all designed compounds possess favorable physicochemical properties, high gastrointestinal absorption, and compliance with Lipinski's Rule of Five. Furthermore, the toxicity profiling categorized the compounds within Class IV (low toxicity), although S3 and S4 displayed predicted hepatotoxicity, necessitating further validation. These findings underscore the potential of dual-target inhibitors as promising candidates for overcoming resistance mechanisms and improving therapeutic outcomes in cancer treatment. Further in vitro and in vivo evaluations are warranted to substantiate their clinical applicability.