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BioAssay: AID 651767

qHTS for Inhibitors of WRN Helicase: Summary

Inhibition of DNA repair is proposed as a strategy for combating cancer. Synthetic lethality is an approach that exploits preexisting DNA repair deficiencies in certain tumors to develop inhibitors of DNA repair pathways that compensate for the tumor-associated DNA repair deficiency. Because helicases play critical roles in the DNA damage response and in DNA repair, particularly in actively more ..
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AID: 651767
Data Source: NCGC (WRN000)
BioAssay Type: Summary, Candidate Probes/Leads with Supporting Evidence
Depositor Category: NIH Molecular Libraries Probe Production Network
Deposit Date: 2012-11-08
Target
Related Experiments
AIDNameTypeComment
651768qHTS for Inhibitors of WRN HelicaseConfirmatorydepositor-specified cross reference
720497qHTS for Inhibitors of WRN Helicase: Confirmatory Assay for Cherry-picked Compounds.Confirmatorydepositor-specified cross reference
720499qHTS for Inhibitors of WRN Helicase: Thiazole Orange DNA Binding CounterscreenConfirmatorydepositor-specified cross reference
720503qHTS for Inhibitors of WRN Helicase: BLM Helicase Counterscreen for WRN InhibitorsConfirmatorydepositor-specified cross reference
Description:
Inhibition of DNA repair is proposed as a strategy for combating cancer. Synthetic lethality is an approach that exploits preexisting DNA repair deficiencies in certain tumors to develop inhibitors of DNA repair pathways that compensate for the tumor-associated DNA repair deficiency. Because helicases play critical roles in the DNA damage response and in DNA repair, particularly in actively dividing and replicating cells, characterization of synthetic lethal relationships of DNA helicases may be of value in developing improved anticancer treatment strategies; moreover, small molecules that specifically target a given DNA helicase may be useful for understanding its role in cellular nucleic acid metabolism. The goal of this project is to identify small molecule, non-covalent chemical inhibitors of the Werner syndrome (WS) helicase (WRN), which plays an important role in cell proliferation, the replication stress response, and DNA repair. Werner syndrome is a premature aging disorder that displays many clinical symptoms of aging at an accelerated rate. The WRN gene product that is defective in the chromosomal instability disorder has DNA helicase and exonuclease activities and interacts with a number of nuclear proteins to maintain genomic stability.

We will employ an optimized high-throughput screening assay that utilizes a fluorescence intensity modulation scheme with a fluorophore and quencher positioned near one another within a duplex deoxyoligonucleotide that contains a single forked structure. After a high-throughput screen of the ~350,000-member Molecular Libraries Small Molecule Repository (MLSMR) collection, followed by data analysis and hit selection, a panel of confirmatory, as well as secondary and ternary, assays will be employed to identify high-confidence WRN inhibitors. Structure-activity relationships will be investigated for the top candidate inhibitor series through medchem expansion. These are the results of the primary screening campaign against the MLSMR.

NIH Chemical Genomics Center [NCGC]
NIH Molecular Libraries Probe Centers Network [MLPCN]

MLPCN Grant: MH096530
Assay Submitter (PI): Robert Brosh, National Institute of Aging
Protocol
Please see linked AIDs for detailed protocols.
Comment
This project is ongoing and will be updated at a later point.
Additional Information
Grant Number: MH096530

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