Structure-based design, synthesis, and biological evaluation of benzofuran derivatives as dual TGF-βR1 and VEGFR2 inhibitors for potent antitumor therapy.

The transforming growth factor-beta receptor type I (TGF-βR1) and vascular endothelial growth factor receptor 2 (VEGFR-2) signaling pathways are crucial for tumorigenesis across multiple cancer types. Evidence indicates that simultaneously targeting these pathways can offer an effective anticancer strategy, potentially overcoming resistance and the inconsistent responses often observed with single-target agents or standard combination therapies. We applied a structure-based design strategy that combined virtual screening, molecular docking, and molecular dynamics (MD) simulations. Using this approach, a series of benzofuran-pyrazole derivatives was designed and synthesized as dual inhibitors of TGF-βR1 and VEGFR-2 signaling. Additionally, in vitro testing identified compound 3b5 as the most potent dual inhibitor, displaying strong antiproliferative effects across various human cancer cell lines. Its impressive performance in the HT-29 colorectal cancer model makes 3b5 a promising candidate for further development.