{"@context":{"@vocab":"https://cir.nii.ac.jp/schema/1.0/","rdfs":"http://www.w3.org/2000/01/rdf-schema#","dc":"http://purl.org/dc/elements/1.1/","dcterms":"http://purl.org/dc/terms/","foaf":"http://xmlns.com/foaf/0.1/","prism":"http://prismstandard.org/namespaces/basic/2.0/","cinii":"http://ci.nii.ac.jp/ns/1.0/","datacite":"https://schema.datacite.org/meta/kernel-4/","ndl":"http://ndl.go.jp/dcndl/terms/","jpcoar":"https://github.com/JPCOAR/schema/blob/master/2.0/"},"@id":"https://cir.nii.ac.jp/crid/1362825895727767040.json","@type":"Article","productIdentifier":[{"identifier":{"@type":"DOI","@value":"10.1158/0008-5472.can-09-1805"}},{"identifier":{"@type":"URI","@value":"https://aacrjournals.org/cancerres/article-pdf/69/19/7739/2614567/7739.pdf"}}],"dc:title":[{"@value":"Identification of a Small Molecule Inhibitor of the Human DNA Repair Enzyme Polynucleotide Kinase/Phosphatase"}],"description":[{"type":"abstract","notation":[{"@value":"<jats:title>Abstract</jats:title>\n               <jats:p>Human polynucleotide kinase/phosphatase (hPNKP) is a 57.1-kDa enzyme that phosphorylates DNA 5′-termini and dephosphorylates DNA 3′-termini. hPNKP is involved in both single- and double-strand break repair, and cells depleted of hPNKP show a marked sensitivity to ionizing radiation. Therefore, small molecule inhibitors of hPNKP should potentially increase the sensitivity of human tumors to γ-radiation. To identify small molecule inhibitors of hPNKP, we modified a novel fluorescence-based assay to measure the phosphatase activity of the protein, and screened a diverse library of over 200 polysubstituted piperidines. We identified five compounds that significantly inhibited hPNKP phosphatase activity. Further analysis revealed that one of these compounds, 2-(1-hydroxyundecyl)-1-(4-nitrophenylamino)-6-phenyl-6,7a-dihydro-1H-pyrrolo[3,4-b]pyridine-5,7(2H,4aH)-dione (A12B4C3), was the most effective, with an IC50 of 0.06 μmol/L. When tested for its specificity, A12B4C3 displayed no inhibition of two well-known eukaryotic protein phosphatases, calcineurin and protein phosphatase-1, or APTX, another human DNA 3′-phosphatase, and only limited inhibition of the related PNKP from Schizosaccharomyces pombe. At a nontoxic dose (1 μmol/L), A12B4C3 enhanced the radiosensitivity of human A549 lung carcinoma and MDA-MB-231 breast adenocarcinoma cells by a factor of two, which was almost identical to the increased sensitivity resulting from shRNA-mediated depletion of hPNKP. Importantly, A12B4C3 failed to increase the radiosensitivity of the hPNKP-depleted cells, implicating hPNKP as the principal cellular target of A12B4C3 responsible for increasing the response to radiation. A12B4C3 is thus a useful reagent for probing hPNKP cellular function and will serve as the lead compound for further development of PNKP-targeting drugs. [Cancer Res 2009;69(19):7739–46]</jats:p>"}]}],"creator":[{"@id":"https://cir.nii.ac.jp/crid/1382825895727767046","@type":"Researcher","foaf:name":[{"@value":"Gary K. Freschauf"}],"jpcoar:affiliationName":[{"@value":"1Experimental Oncology, Cross Cancer Institute, and Departments of"},{"@value":"2Oncology,"}]},{"@id":"https://cir.nii.ac.jp/crid/1382825895727767048","@type":"Researcher","foaf:name":[{"@value":"Feridoun Karimi-Busheri"}],"jpcoar:affiliationName":[{"@value":"1Experimental Oncology, Cross Cancer Institute, and Departments of"},{"@value":"2Oncology,"}]},{"@id":"https://cir.nii.ac.jp/crid/1382825895727766912","@type":"Researcher","foaf:name":[{"@value":"Agnieszka Ulaczyk-Lesanko"}],"jpcoar:affiliationName":[{"@value":"3Chemistry, and"}]},{"@id":"https://cir.nii.ac.jp/crid/1382825895727767044","@type":"Researcher","foaf:name":[{"@value":"Todd R. Mereniuk"}],"jpcoar:affiliationName":[{"@value":"1Experimental Oncology, Cross Cancer Institute, and Departments of"},{"@value":"2Oncology,"}]},{"@id":"https://cir.nii.ac.jp/crid/1382825895727766914","@type":"Researcher","foaf:name":[{"@value":"Ashley Ahrens"}],"jpcoar:affiliationName":[{"@value":"1Experimental Oncology, Cross Cancer Institute, and Departments of"},{"@value":"2Oncology,"}]},{"@id":"https://cir.nii.ac.jp/crid/1382825895727766913","@type":"Researcher","foaf:name":[{"@value":"Jonathan M. Koshy"}],"jpcoar:affiliationName":[{"@value":"1Experimental Oncology, Cross Cancer Institute, and Departments of"},{"@value":"2Oncology,"}]},{"@id":"https://cir.nii.ac.jp/crid/1382825895727767045","@type":"Researcher","foaf:name":[{"@value":"Aghdass Rasouli-Nia"}],"jpcoar:affiliationName":[{"@value":"1Experimental Oncology, Cross Cancer Institute, and Departments of"},{"@value":"2Oncology,"}]},{"@id":"https://cir.nii.ac.jp/crid/1382825895727767043","@type":"Researcher","foaf:name":[{"@value":"Phuwadet Pasarj"}],"jpcoar:affiliationName":[{"@value":"4Biochemistry, University of Alberta, Edmonton, Alberta, Canada; and"}]},{"@id":"https://cir.nii.ac.jp/crid/1382825895727767040","@type":"Researcher","foaf:name":[{"@value":"Charles F.B. Holmes"}],"jpcoar:affiliationName":[{"@value":"4Biochemistry, University of Alberta, Edmonton, Alberta, Canada; and"}]},{"@id":"https://cir.nii.ac.jp/crid/1382825895727767042","@type":"Researcher","foaf:name":[{"@value":"Frauke Rininsland"}],"jpcoar:affiliationName":[{"@value":"5QTL Biosystems, Santa Fe, New Mexico"}]},{"@id":"https://cir.nii.ac.jp/crid/1382825895727767041","@type":"Researcher","foaf:name":[{"@value":"Dennis G. Hall"}],"jpcoar:affiliationName":[{"@value":"3Chemistry, and"}]},{"@id":"https://cir.nii.ac.jp/crid/1382825895727767047","@type":"Researcher","foaf:name":[{"@value":"Michael Weinfeld"}],"jpcoar:affiliationName":[{"@value":"1Experimental Oncology, Cross Cancer Institute, and Departments of"},{"@value":"2Oncology,"}]}],"publication":{"publicationIdentifier":[{"@type":"PISSN","@value":"00085472"},{"@type":"EISSN","@value":"15387445"}],"prism:publicationName":[{"@value":"Cancer Research"}],"dc:publisher":[{"@value":"American Association for Cancer Research (AACR)"}],"prism:publicationDate":"2009-10-01","prism:volume":"69","prism:number":"19","prism:startingPage":"7739","prism:endingPage":"7746"},"reviewed":"false","url":[{"@id":"https://aacrjournals.org/cancerres/article-pdf/69/19/7739/2614567/7739.pdf"}],"createdAt":"2009-09-23","modifiedAt":"2022-06-17","relatedProduct":[{"@id":"https://cir.nii.ac.jp/crid/1360025430196865664","@type":"Article","resourceType":"学術雑誌論文(journal article)","relationType":["isReferencedBy"],"jpcoar:relatedTitle":[{"@value":"CDK-mediated phosphorylation of PNKP is required for end-processing of single-strand DNA gaps on Okazaki fragments and genome stability"}]},{"@id":"https://cir.nii.ac.jp/crid/1360290617597773824","@type":"Article","resourceType":"学術雑誌論文(journal article)","relationType":["isReferencedBy"],"jpcoar:relatedTitle":[{"@value":"The FHA domain of PNKP is essential for its recruitment to DNA damage sites and maintenance of genome stability"}]},{"@id":"https://cir.nii.ac.jp/crid/1360857593766702336","@type":"Article","resourceType":"preprint","relationType":["isReferencedBy"],"jpcoar:relatedTitle":[{"@value":"CDKs-mediated phosphorylation of PNKP is required for end-processing of single-strand DNA gaps on Okazaki Fragments and genome stability"}]}],"dataSourceIdentifier":[{"@type":"CROSSREF","@value":"10.1158/0008-5472.can-09-1805"},{"@type":"CROSSREF","@value":"10.1101/2021.07.29.452278_references_DOI_8yGHxQ9AAgjsHFR2d9jto9R1VOY"},{"@type":"CROSSREF","@value":"10.7554/elife.99217_references_DOI_8yGHxQ9AAgjsHFR2d9jto9R1VOY"},{"@type":"CROSSREF","@value":"10.1016/j.mrfmmm.2020.111727_references_DOI_8yGHxQ9AAgjsHFR2d9jto9R1VOY"}]}