title: Identification of a Small Molecule Inhibitor of RAD52 by Structure-Based Selection.
abstract: It has been reported that inhibition of RAD52 either by specific shRNA or a small peptide aptamer induced synthetic lethality in tumor cell lines carrying BRCA1 and BRCA2 inactivating mutations. Molecular docking was used to screen two chemical libraries: 1) 1,217 FDA approved drugs, and 2) 139,735 drug-like compounds to identify candidates for interacting with DNA binding domain of human RAD52. Thirty six lead candidate compounds were identified that were predicted to interfere with RAD52 -DNA binding. Further biological testing confirmed that 9 of 36 candidate compounds were able to inhibit the binding of RAD52 to single-stranded DNA in vitro. Based on molecular binding combined with functional assays, we propose a model in which the active compounds bind to a critical "hotspot" in RAD52 DNA binding domain 1. In addition, one of the 9 active compounds, adenosine 5'-monophosphate (A5MP), and also its mimic 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) 5' phosphate (ZMP) inhibited RAD52 activity in vivo and exerted synthetic lethality against BRCA1 and BRCA2-mutated carcinomas. These data suggest that active, inhibitory RAD52 binding compounds could be further refined for efficacy and safety to develop drugs inducing synthetic lethality in tumors displaying deficiencies in BRCA1/2-mediated homologous recombination.
authors.affiliation: Department of Microbiology and Immunology and Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, Philadelphia, Pennsylvania 19140, United States of America.
authors.forename: Katherine
authors.initials: K
authors.lastname: Sullivan
authors.affiliation: Department of Microbiology and Immunology and Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, Philadelphia, Pennsylvania 19140, United States of America.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Cramer-Morales
authors.affiliation: Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida & Shands, Gainesville, Florida 32610, United States of America.
authors.forename: Daniel L
authors.initials: DL
authors.lastname: McElroy
authors.affiliation: Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida & Shands, Gainesville, Florida 32610, United States of America.
authors.forename: David A
authors.initials: DA
authors.lastname: Ostrov
authors.affiliation: Moulder Center for Drug Discovery Research, Temple University School of Pharmacy, Philadelphia, Pennsylvania 19140, United States of America.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Haas
authors.affiliation: Moulder Center for Drug Discovery Research, Temple University School of Pharmacy, Philadelphia, Pennsylvania 19140, United States of America.
authors.forename: Wayne
authors.initials: W
authors.lastname: Childers
authors.affiliation: Department of Medicine, College of Medicine, University of Florida & Shands, Gainesville, Florida 32610, United States of America.
authors.forename: Robert
authors.initials: R
authors.lastname: Hromas
authors.affiliation: Department of Microbiology and Immunology and Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, Philadelphia, Pennsylvania 19140, United States of America.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Skorski
mesh_terms: D019313:BRCA1 Protein / Q000172:deficiency / Q000235:genetics; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D004277:DNA, Single-Stranded / Q000378:metabolism*; D005260:Female; D018095:Germ-Line Mutation / Q000235:genetics; D006801:Humans; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D011487:Protein Conformation; D051721:Rad52 DNA Repair and Recombination Protein / Q000737:chemistry* / Q000378:metabolism*; D054852:Small Molecule Libraries / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D004277:DNA, Single-Stranded; C497194:RAD52 protein, human; D051721:Rad52 DNA Repair and Recombination Protein; D054852:Small Molecule Libraries