title: Pharmacophore guided discovery of small-molecule human apurinic/apyrimidinic endonuclease 1 inhibitors.
abstract: Human apurinic/apyrimidinic endonuclease 1 (APE1) is an important enzyme in the base excision repair (BER) pathway that is essential for the repair of abasic sites in the genome. Evidence for APE1 as an attractive therapeutic target in anticancer drug development has been demonstrated by studies that link overexpression of APE1 in many cancers to resistance of tumor cells to radio- and chemotherapy. APE1 also shows a protective effect in several cancer cell models to a variety of DNA damaging agents. This study represents the first rational design of selective small-molecule APE1 inhibitors utilizing a three-dimensional interaction-based pharmacophore perception. All of our most potent molecules show inhibitory activity below 10 muM and are selective for APE1 inhibition.
authors.affiliation: Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, California 90033, USA.
authors.forename: Zahrah
authors.initials: Z
authors.lastname: Zawahir
authors.forename: Raveendra
authors.initials: R
authors.lastname: Dayam
authors.forename: Jinxia
authors.initials: J
authors.lastname: Deng
authors.forename: Cherelene
authors.initials: C
authors.lastname: Pereira
authors.forename: Nouri
authors.initials: N
authors.lastname: Neamati
mesh_terms: D055162:Biocatalysis; D020650:Combinatorial Chemistry Techniques; D018360:Crystallography, X-Ray; D004247:DNA / Q000737:chemistry / Q000378:metabolism; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D004247:DNA; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase