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dc.contributor.authorStowell, Alexandra I J
dc.contributor.authorJames, Dominic I
dc.contributor.authorWaddell, Ian D
dc.contributor.authorBennett, N
dc.contributor.authorTruman, C
dc.contributor.authorHardern, I
dc.contributor.authorOgilvie, Donald J
dc.date.accessioned2016-04-22T15:07:03Zen
dc.date.available2016-04-22T15:07:03Zen
dc.date.issued2016-03-29en
dc.identifier.citationAn HTS-compatible HTRF assay measuring the glycohydrolase activity of human PARG. 2016: Anal Biochemen
dc.identifier.issn1096-0309en
dc.identifier.pmid27036617en
dc.identifier.doi10.1016/j.ab.2016.03.016en
dc.identifier.urihttp://hdl.handle.net/10541/606644en
dc.description.abstractPoly(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.
dc.languageENGen
dc.language.isoenen
dc.rightsArchived with thanks to Analytical biochemistryen
dc.titleAn HTS-compatible HTRF assay measuring the glycohydrolase activity of human PARG.en
dc.typeArticleen
dc.contributor.departmentCancer Research UK Manchester Institute Drug Discovery Unit, University of Manchester, Manchester,en
dc.identifier.journalAnalytical Biochemistryen
html.description.abstractPoly(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.


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