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BioAssay: AID 2367

Probe Development Summary for Inhibitors of RecQ-Like Dna Helicase 1 (RECQ1)

Survival of cells and the faithful propagation of the genome depend on elaborate mechanisms of detecting and repairing DNA damage. Treatment of advanced cancer relies on radiation therapy or chemotherapy, which kill cancer cells by causing extensive DNA damage. It is often found, that cancer cells develop resistance to therapy through enhanced activity of DNA repair functions; this has led to an increased interest in developing drugs that interfere with DNA repair, which could sensitise cancer cells to conventional therapy. ..more
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AID: 2367
Data Source: NCGC (RECQ100)
BioAssay Type: Summary, Candidate Probes/Leads with Supporting Evidence
Depositor Category: NIH Molecular Libraries Probe Production Network
Deposit Date: 2010-02-16
Target
Depositor Specified Assays
AIDNameTypeComment
2353qHTS Validation Assay for Inhibitors of RecQ-Like Dna Helicase 1 (RECQ1)confirmatoryvalidation qHTS assay for inhibitors of human RECQ1
2549qHTS Assay for Inhibitors of RecQ-Like Dna Helicase 1 (RECQ1)confirmatory
2708Confirmation qHTS Assay for Inhibitors of RecQ-Like Dna Helicase 1 (RECQ1)confirmatory
2711Counterscreen for RECQ1 Inhibitors: ADP Fluorescence Polarization Displacement Assayconfirmatory
504841Confirmation qHTS Assay for Inhibitors of RecQ-Like Dna Helicase 1 (RECQ1) - Round 2 Cherry Picksconfirmatory
Description:
Survival of cells and the faithful propagation of the genome depend on elaborate mechanisms of detecting and repairing DNA damage. Treatment of advanced cancer relies on radiation therapy or chemotherapy, which kill cancer cells by causing extensive DNA damage. It is often found, that cancer cells develop resistance to therapy through enhanced activity of DNA repair functions; this has led to an increased interest in developing drugs that interfere with DNA repair, which could sensitise cancer cells to conventional therapy.

This summary assay pertains to human RECQ1, which is important in resolving abnormal DNA structures formed during replication or homologous recombination. Shutting down the expression of RECQ1 leads to chromosomal instability and higher radiation sensitivity in cultured cells. Remarkably, some cancer cell lines, but not normal cells, exhibit reduced growth and an increase in cell death when RECQ1 expression is inhibited by RNAi.

The goal of this project is to develop inhibitors of RECQ1 activity, which can be used in cell and animal models to examine the consequences of inhibition on the survival of cancer cells. Initial candidates will be identified by a quantitative high-throughput screen (qHTS) of the MLSMR compound library, using a fluorescence-based in vitro biochemical assay that reveals inhibitors of RECQ1 DNA unwinding activity. The resulting compounds will then be subject to orthogonal, secondary biochemical assays, to triage the initial hits, to classify compounds based on mode of action, and to derive structure#activity relationships (SARs) of candidate effectors. SAR and protein structural information will be used in further chemical development to improve the potency and selectivity of the compounds. Cell-based assays will then be applied as the first step in utilizations of the verified inhibitors, examining their effects on cancer cell survival and sensitivity to radiation and chemotherapeutics.

This assay will summarize the probe development efforts that are currently ongoing.

Assay Providers:
Opher Gileadi, Structural Genomics Consortium, University of Oxford
Alessandro Vindigni, International Center for Biotechnology and Genetic Engineering

Screening Center PI: Austin, C.P.
Screening Center: NIH Chemical Genomics Center [NCGC]
Protocol
Related BioAssays and their individual protocols will be added in PubChem, and this summary assay will be updated to reflect those changes.
Comment
Keywords, RECQL, RecQ protein-like (DNA helicase Q1-like), RECQL1, Member of the RecQ DNA helicase family
Additional Information
Grant Number: MH087284-01

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