DESIGN AND SYNTHESIS OF SMALL MOLECULE INHIBITORS TARGETING ONCOGENIC PATHWAYS IN CANCER THERAPY

Abstract

Small molecule inhibitors (SMIs) of oncogenic pathways have been shown to be promising anticancer drugs because they can specifically target receptor tyrosine kinases (RTKs) that are implicated in tumor growth, survival, and metastasis. In this article, the design, synthesis, and biological evaluation of new SMIs targeting EGFR, HER2, and VEGFR, which are aberrantly expressed in cancers, are explored.The lead compounds were designed by structure-based drug design and were optimized for potency and selectivity through the execution of structure-activity relationship (SAR) studies. The lead compounds were demonstrated to possess strong inhibitory activity in in vitro kinase assays having IC50 values in the subnanomolar range. Further, the lead compounds inhibited selectively proliferation of cancer cells but not normal cells and induced apoptosis through intrinsic and extrinsic pathways. In vivo studies using xenograft models of breast and non-small cell lung cancer showed significant tumor inhibition with low systemic toxicity. Bioavailability and metabolic stability were excellent according to pharmacokinetic analysis, which favors the therapeutic use of the compounds. Secondary mutations and activation of compensatory pathways constituted mechanisms of resistance, which suggest the use of combination therapies and second-generation inhibitors.This research provides a full blueprint for the design of selective and effective SMIs against oncogenic RTKs, which promises personalized cancer therapy. Future directions include optimizing combination regimens, exploring response biomarkers, and developing next-generation inhibitors with improved selectivity and reduced toxicity.