Issues

DNA polymerase β (Pol-β) is involved in base excision repair and is considered to be a key target for chemotherapeutic strategies. Using a novel structure-based selection approach, approximately 140,000 small drug-like molecules were screened for their abilities to bind Pol-β. One drug, 3-sulfanylidenespiro[2,5-dihydro-1H-[1,2,4]triazolo[4,3-b][1,2,4]triazine-6,9′-fluorene]-7-one (NSC-666715), was found to inhibit Pol-β-directed single-nucleotide and long-patch base excision repair activities in vitro and have dramatic anticancer effects in vivo. The molecular surface of Pol-β is colored gold for Thr79, blue for Lys81, purple for Arg83, gray for other residues. Magenta spheres depict the site selected for molecular docking. NSC-666175 is shown as sticks; yellow for carbon, red for oxygen, blue for nitrogen, white for hydrogen, green for sulfur. For details, see article by Jaiswal and colleagues on page 1973 .