GDK-100017, a 2,3,6-trisubstituted quinoxaline derivative, reduced p-catenin-T-cell factor/lymphoid enhancer factor (TCF/LEF)-dependent transcriptional activity and inhibited cell proliferation in a dose-dependent manner with an IC50 value of about 10 mu M in A549/Wnt2 cells. GDK-100017 down-regulated the expression of Wnt/beta-catenin pathway target genes such as cyclin D1 and Dkkl but not c-myc or survivin. GDK-100017 inhibited cell proliferation by arresting the cell cycle in the G1 phase not only in A549/wnt2 cells but also in SW480 colon cancer cells. In addition to its wnt signaling inhibitory properties, GDK-100017 also enhanced the radiosensitivity of the A549 human NSCLC line. These results suggest that GDK-100017 possesses potential anti-cancer activity by inhibiting the Wnt/beta-catenin signal pathway, blocking the beta-catenin-TCF/LEF interaction, and enhancing radiosensitivity. (C) 2013 Elsevier Inc. All rights reserved.