Structure-Based Design and Free Energy Perturbation-Guided Synthesis of Novel VEGFR2 and HDAC Dual Inhibitors with Potent Antitumor Efficacy

The development of dual-targeted inhibitors represents a promising strategy to address the challenges of drug resistance and limited efficacy in cancer therapy. This study describes the design, synthesis, and evaluation of novel inhibitors targeting VEGFR2 and HDAC through a structure-based pharmacophore-merging strategy. We integrated the hydroxamic acid zinc-binding group and the linker into the back pocket of VEGFR2. Molecular dynamics (MD) simulations and free energy perturbation (FEP) calculations facilitated the optimization of the inhibitors, ultimately leading to the discovery of compound <b>10i</b>, which demonstrated significant dual-inhibitory activity. <i>In vitro</i> assays demonstrated its potent antiproliferative effects against cancer cell lines, particularly HT-29, while maintaining a favorable safety profile for normal cells. <i>In vivo</i> evaluation using HT-29 and HCCLM3/Sorafenib xenograft models confirmed robust tumor growth inhibition (TGI = 64.40% and 89.72%), with no significant toxicity observed. These findings underscore the therapeutic potential of compound <b>10i</b> as a VEGFR2/HDAC dual inhibitor.