Discovery of Novel Piperidinyl-Based Benzoxazole Derivatives as Anticancer Agents Targeting VEGFR-2 and c-Met Kinases

<b>Background/Objectives</b>: A promising anticancer strategy is the simultaneous inhibition of the receptor tyrosine kinases VEGFR-2 and c-Met, which are essential for tumor angiogenesis, growth, and metastasis. In this study, a novel series of piperidinyl-based benzoxazole derivatives was designed and synthesized as potential dual VEGFR-2/c-Met inhibitors. <b>Methods</b>: The kinase inhibitory potential of the derivatives was evaluated in comparison to reference inhibitors, Sorafenib (VEGFR-2 inhibitor) and Staurosporine (c-Met inhibitor). Cytotoxicity was assessed across breast, prostate (PC-3), and lung (A549) cancer cell lines. Mechanistic studies included cell-cycle analysis, apoptosis assays, gene expression profiling of apoptosis-related markers, and molecular docking within the ATP-binding pockets of both kinases. <b>Results</b>: Compounds <b>5a</b>, <b>5g</b>, <b>5h</b>, <b>11a</b>, and <b>11b</b> showed strong inhibition of both kinases (IC₅₀ = 0.145-0.970 μM for VEGFR-2 and 0.181-1.885 μM for c-Met). Selective cytotoxicity was observed against breast cancer cells, with compound <b>11b</b> (<i>p</i>-fluorophenyl derivative) exhibiting high selectivity toward MCF-7 over normal breast cells (MCF-10A) and potency comparable to or exceeding Sorafenib. Mechanistically, <b>11b</b> induced G₂/M cell-cycle arrest and apoptosis (total apoptosis = 48.34%), accompanied by upregulation of p53, BAX, and caspase-9 and downregulation of Bcl-2. Molecular docking confirmed stable binding within the ATP-binding sites of both kinases. <b>Conclusions</b>: Compound <b>11b</b> was established as a novel, selective, dual VEGFR-2/c-Met inhibitor with strong potential for targeted breast cancer therapy.