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Accepted (AM)Open Access (License Unspecified), Open
Journal article
Identification of specific inhibitors of human RAD51 recombinase using high-throughput screening
ACS chemical biology, v 6(6), pp 628-635
23 Mar 2011
PMID: 21428443
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
RAD51 is a key protein of homologous recombination that plays a critical role in the repair of DNA double-strand breaks (DSB) and interstrand cross links (ICL). To better understand the cellular function(s) of human RAD51, we propose to develop specific RAD51 inhibitors. RAD51 inhibitors may also help to increase the potency of anticancer drugs that act by inducing DSBs or ICLs, e.g., cisplatin or ionizing radiation.
In vitro,
RAD51 promotes DNA strand exchange between homologous ss- and dsDNA. Here, we developed a DNA strand exchange assay based on fluorescence resonance energy transfer and used this assay to identify RAD51 inhibitors by high throughput screening of the NIH Small Molecule Repository (>200,000 compounds). Seventeen RAD51 inhibitors were identified and analyzed for selectivity using additional non-fluorescent DNA-based assays. As a result, we identified a compound (
B02
) that specifically inhibited human RAD51 (IC
50
= 27.4 μM), but not its
E. coli
homologue RecA (IC
50
> 250 μM). Two other compounds (A03 and A10) were identified that inhibited both RAD51 and RecA, but not the structurally unrelated RAD54 protein. The structure-activity relationship (SAR) analysis allowed us to identify the structural components of
B02
that are critical for RAD51 inhibition. The described approach can be used for identification of specific inhibitors of other human proteins that play an important role in DNA repair, e.g., RAD54 or Bloom’s syndrome helicase.
Metrics
Details
- Title
- Identification of specific inhibitors of human RAD51 recombinase using high-throughput screening
- Creators
- Fei Huang - Drexel UniversityNuzhat A. Motlekar - University of PennsylvaniaChelsea M. Burgwin - Drexel UniversityAndrew D. Napper - University of PennsylvaniaScott L. Diamond - University of PennsylvaniaAlexander V. Mazin - Drexel University
- Publication Details
- ACS chemical biology, v 6(6), pp 628-635
- Publisher
- American Chemical Society; Washington, DC
- Grant note
- R03 MH084119-01 || MH / National Institute of Mental Health : NIMH R01 CA100839-08 || CA / National Cancer Institute : NCI
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Biochemistry and Molecular Biology
- Web of Science ID
- WOS:000291896400013
- Scopus ID
- 2-s2.0-79961077772
- Other Identifier
- 991019168065904721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Biochemistry & Molecular Biology