Novel approaches to improving the therapeutic options of renal cell carcinomas are urgently needed. Here, a conformational drug database was used to search for novel antiangiogenic compounds as innovative drugs for renal cancer treatment. Checking two- and three-dimensional structural similarities to the clinically relevant VEGFR inhibitor, vatalanib, as lead structure revealed 14 promising candidate drugs. In vitro evaluations revealed 2 compounds with superior antiproliferative effects on renal cell cancer and endothelial cells, as compared to vatalanib. Both compounds exhibited antiangiogenic and antimigratory effects on endothelial cells and renal cell carcinoma cells. First data show that the mode of action involves the induction of cell cycle arrest and apoptosis, while unspecific cytotoxicity does not contribute to the antineoplastic effects. CAM-assays confirmed the antiangiogenic effects of both compounds in vivo. Moreover, first animal studies showed a good tolerability of the compounds when given in 48h intervals at concentrations of up to 50mg/kg. The identification of novel cancer drugs by use of in silico methods is a target-oriented and effective approach. The identified compounds are very promising and merit further elucidation.