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BioAssay: AID 2386

Probe Development Summary for Inhibitors of Bloom's syndrome helicase (BLM)

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 sensitize cancer cells to conventional therapy. ..more
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AID: 2386
Data Source: NCGC (BLMA100)
BioAssay Type: Summary, Candidate Probes/Leads with Supporting Evidence
Depositor Category: NIH Molecular Libraries Probe Production Network
BioAssay Version:
Deposit Date: 2010-02-19
Modify Date: 2010-03-15
Target
Sequence: Bloom syndrome protein [Homo sapiens]
Description ..   
Protein Family: HELICc

Gene:BLM     Related Protein 3D Structures     More BioActivity Data..
Depositor Specified Assays
Show more
AIDNameTypeComment
2364qHTS Validation Assay for Inhibitors of Bloom's syndrome helicase (BLM)confirmatoryqHTS Validation Assay for Inhibitors of Bloom's syndrome helicase (BLM)
2528qHTS Assay for Inhibitors of Bloom's syndrome helicase (BLM)confirmatoryqHTS Primary Assay for Inhibitors of Bloom's syndrome helicase (BLM)
2585qHTS Confirmation Assay for Inhibitors of Bloom's syndrome helicase (BLM)confirmatory
2712Counterscreen for BLMA Inhibitors: ADP Fluorescence Polarization Displacement Assayconfirmatory
504662Inhibitors of BLM Helicase: DNA Unwinding Measured by Gel Electrophoresis - BLM Helicase Activityconfirmatory
504663Inhibitors of BLM Helicase: DNA Unwinding Measured by Gel Electrophoresis - RecQL1 Helicase Counterscreenconfirmatory
504736Inhibitors of Bloom's syndrome helicase: Efflux Ratio Profiling Assayother
504737Inhibitors of Bloom's syndrome helicase: Caco-2 Permeability Profiling Assayother
504738Inhibitors of Bloom's syndrome helicase: Aqueous Profiling Assayother
504739Inhibitors of Bloom's syndrome helicase: Metabolic Stability Profilingother
504740Inhibitors of Bloom's syndrome helicase: Mouse Plasma Stability Profilingother
504741Inhibitors of Bloom's syndrome helicase: PBS Stability Profiling Assayother
720549On Hold
720550On Hold
720555On Hold
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 sensitize cancer cells to conventional therapy.

This summary assay pertains to the Bloom syndrome helicase (BLM), which is important in resolving abnormal DNA structures formed during replication or homologous recombination. Shutting down the expression of BLM leads to chromosomal instability and higher radiation sensitivity in cultured cells.

The goal of this project is to develop inhibitors of BLM 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 BLM 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:
Ian Hickson, University of Oxford
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
Please see related BioAssays for all protocols relevant to this probe development project: AIDs 2364, 2528

Additional related BioAssays and their individual protocols will be added in PubChem, and this summary assay will be updated to reflect those changes.
Comment
Keywords, BLMA, RecQ Helicase, RecQ-like type 2, Bloom syndrome protein
Additional Information
Grant Number: MH087284-01

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