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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..
Related Experiments
Show more
AIDNameTypeComment
2364qHTS Validation Assay for Inhibitors of Bloom's syndrome helicase (BLM)Confirmatorydepositor-specified cross reference: qHTS Validation Assay for Inhibitors of Bloom's syndrome helicase (BLM)
2528qHTS Assay for Inhibitors of Bloom's syndrome helicase (BLM)Confirmatorydepositor-specified cross reference: qHTS Primary Assay for Inhibitors of Bloom's syndrome helicase (BLM)
2585qHTS Confirmation Assay for Inhibitors of Bloom's syndrome helicase (BLM)Confirmatorydepositor-specified cross reference
2712Counterscreen for BLMA Inhibitors: ADP Fluorescence Polarization Displacement AssayConfirmatorydepositor-specified cross reference
504662Inhibitors of BLM Helicase: DNA Unwinding Measured by Gel Electrophoresis - BLM Helicase ActivityConfirmatorydepositor-specified cross reference
504663Inhibitors of BLM Helicase: DNA Unwinding Measured by Gel Electrophoresis - RecQL1 Helicase CounterscreenConfirmatorydepositor-specified cross reference
504736Inhibitors of Bloom's syndrome helicase: Efflux Ratio Profiling AssayOtherdepositor-specified cross reference
504737Inhibitors of Bloom's syndrome helicase: Caco-2 Permeability Profiling AssayOtherdepositor-specified cross reference
504738Inhibitors of Bloom's syndrome helicase: Aqueous Profiling AssayOtherdepositor-specified cross reference
504739Inhibitors of Bloom's syndrome helicase: Metabolic Stability ProfilingOtherdepositor-specified cross reference
504740Inhibitors of Bloom's syndrome helicase: Mouse Plasma Stability ProfilingOtherdepositor-specified cross reference
504741Inhibitors of Bloom's syndrome helicase: PBS Stability Profiling AssayOtherdepositor-specified cross reference
720549qHTS for Inhibitors of Bloom's syndrome helicase (BLM): Helicase ATPase Orthogonal Confirmatory Assay for SAROtherdepositor-specified cross reference
720550qHTS for Inhibitors of Bloom's syndrome helicase (BLM): Thiazole Orange DNA Binding Counterscreen for SAR.Otherdepositor-specified cross reference
720555qHTS for Inhibitors of Bloom's syndrome helicase (BLM): Helicase DNA unwinding fluorescent orthogonal confirmatory assay for SAROtherdepositor-specified cross reference
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
Categorized Comment - additional comments and annotations
From MLP Probe Report:
Probe count: 1
MLP Probe ML# for probe 1: ML216
PubChem Substance ID (SID) for probe 1: 104222022
PubChem Compound ID (CID) for probe 1: 49852229
Probe type for probe 1: Inhibitor
Target for probe 1: BLM Helicase (gi: 4557365)
Anti-target for probe 1: RecQL1 Helicase
Fold selectivity for probe 1: >36
NCBI Book chapter link for probe 1: http://www.ncbi.nlm.nih.gov/books/NBK154497/ (ID: 3050928)
Grant number for probe 1: MH087284-01
NCBI Book chapter title for probe 1: Discovery of ML216, a Small Molecule Inhibitor of Bloom (BLM) Helicase
Additional Information
Grant Number: MH087284-01

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