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Identification of a Small Molecule Inhibitor of RAD52 by Structure-Based Selection
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...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4718542/ https://www.ncbi.nlm.nih.gov/pubmed/26784987 http://dx.doi.org/10.1371/journal.pone.0147230 |
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author | Sullivan, Katherine Cramer-Morales, Kimberly McElroy, Daniel L. Ostrov, David A. Haas, Kimberly Childers, Wayne Hromas, Robert Skorski, Tomasz |
author_facet | Sullivan, Katherine Cramer-Morales, Kimberly McElroy, Daniel L. Ostrov, David A. Haas, Kimberly Childers, Wayne Hromas, Robert Skorski, Tomasz |
author_sort | Sullivan, Katherine |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-4718542 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-47185422016-01-30 Identification of a Small Molecule Inhibitor of RAD52 by Structure-Based Selection Sullivan, Katherine Cramer-Morales, Kimberly McElroy, Daniel L. Ostrov, David A. Haas, Kimberly Childers, Wayne Hromas, Robert Skorski, Tomasz PLoS One Research Article 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. Public Library of Science 2016-01-19 /pmc/articles/PMC4718542/ /pubmed/26784987 http://dx.doi.org/10.1371/journal.pone.0147230 Text en © 2016 Sullivan et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Sullivan, Katherine Cramer-Morales, Kimberly McElroy, Daniel L. Ostrov, David A. Haas, Kimberly Childers, Wayne Hromas, Robert Skorski, Tomasz Identification of a Small Molecule Inhibitor of RAD52 by Structure-Based Selection |
title | Identification of a Small Molecule Inhibitor of RAD52 by Structure-Based Selection |
title_full | Identification of a Small Molecule Inhibitor of RAD52 by Structure-Based Selection |
title_fullStr | Identification of a Small Molecule Inhibitor of RAD52 by Structure-Based Selection |
title_full_unstemmed | Identification of a Small Molecule Inhibitor of RAD52 by Structure-Based Selection |
title_short | Identification of a Small Molecule Inhibitor of RAD52 by Structure-Based Selection |
title_sort | identification of a small molecule inhibitor of rad52 by structure-based selection |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4718542/ https://www.ncbi.nlm.nih.gov/pubmed/26784987 http://dx.doi.org/10.1371/journal.pone.0147230 |
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