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    An HTS-compatible HTRF assay measuring the glycohydrolase activity of human PARG.

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    Authors
    Stowell, Alexandra I J
    James, Dominic I
    Waddell, Ian D
    Bennett, N
    Truman, C
    Hardern, I
    Ogilvie, Donald J
    Affiliation
    Cancer Research UK Manchester Institute Drug Discovery Unit, University of Manchester, Manchester,
    Issue Date
    2016-03-29
    
    Metadata
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    Abstract
    Poly(ADP-ribose)(PAR) polymers are transient post-translational modifications, and their formation is catalyzed by poly(ADP-ribose) polymerase (PARP) enzymes. A number of PARP inhibitors are in advanced clinical development for BRCA-mutated breast cancer, and olaparib has recently been approved for BRCA-mutant ovarian cancer; however, there has already been evidence of developed resistance mechanisms. Poly(ADP-ribose) glycohydrolase (PARG) catalyzes the hydrolysis of the endo- and exo-glycosidic bonds within the PAR polymers. As an alternative strategy, PARG is a potentially attractive therapeutic target. There is only one PARG gene, compared with 17 known PARP family members, and therefore a PARG inhibitor may have wider application with fewer compensatory mechanisms. Prior to the initiation of this project, there were no known existing cell-permeable small molecule PARG inhibitors for use as tool compounds to assess these hypotheses, and no suitable high-throughput screening (HTS)-compatible biochemical assays available to identify start points for a drug discovery project. The development of this newly-described high-throughput homogeneous time-resolved fluorescence (HTRF) assay has allowed HTS to proceed, and from this, the identification and advancement of multiple validated series of tool compounds for PARG inhibition.
    Citation
    An HTS-compatible HTRF assay measuring the glycohydrolase activity of human PARG. 2016: Anal Biochem
    Journal
    Analytical Biochemistry
    URI
    http://hdl.handle.net/10541/606644
    DOI
    10.1016/j.ab.2016.03.016
    PubMed ID
    27036617
    Type
    Article
    Language
    en
    ISSN
    1096-0309
    ae974a485f413a2113503eed53cd6c53
    10.1016/j.ab.2016.03.016
    Scopus Count
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    All Paterson Institute for Cancer Research

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