Design, Synthesis, and Structure-Activity Relationships of Pyridoquinazolinecarboxamides as RNA Polymerase I Inhibitors

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dc.contributor.author Colis, Laureen
dc.contributor.author Ernst, Glen
dc.contributor.author Sanders, Sara
dc.contributor.author Liu, Hester
dc.contributor.author Sirajuddin, Paul
dc.contributor.author Peltonen, Karita
dc.contributor.author DePasquale, Michael
dc.contributor.author Barrow, James C.
dc.contributor.author Laiho, Marikki
dc.date.accessioned 2017-09-21T13:20:00Z
dc.date.available 2017-09-21T13:20:00Z
dc.date.issued 2014-06-12
dc.identifier.citation Colis , L , Ernst , G , Sanders , S , Liu , H , Sirajuddin , P , Peltonen , K , DePasquale , M , Barrow , J C & Laiho , M 2014 , ' Design, Synthesis, and Structure-Activity Relationships of Pyridoquinazolinecarboxamides as RNA Polymerase I Inhibitors ' , Journal of Medicinal Chemistry , vol. 57 , no. 11 , pp. 4950-4961 . https://doi.org/10.1021/jm5004842
dc.identifier.other PURE: 56055517
dc.identifier.other PURE UUID: e85efa02-815e-4d01-8d44-a964114b53e4
dc.identifier.other WOS: 000337336600039
dc.identifier.other Scopus: 84902476120
dc.identifier.other ORCID: /0000-0002-3063-451X/work/39897485
dc.identifier.uri http://hdl.handle.net/10138/224460
dc.description.abstract RNA polymerase I (Pol I) is a dedicated polymerase that transcribes the 45S ribosomal (r) RNA precursor. The 45S rRNA precursor is subsequently processed into the mature 5.8S, 18S, and 28S rRNAs and assembled into ribosomes in the nucleolus. Pol I activity is commonly deregulated in human cancers. On the basis of the discovery of lead molecule BMH-21, a series of pyridoquinazolinecarboxamides have been evaluated as inhibitors of Pol I and activators of the destruction of RPA194, the Poll large catalytic subunit protein. Structure-activity relationships in assays of nucleolar stress and cell viability demonstrate key pharmacophores and their physicochemical properties required for potent activation of Pol I stress and cytotoxidty. This work identifies a set of bioactive compounds that potently cause RPA194 degradation that function in a tightly constrained chemical space. This work has yielded novel derivatives that contribute to the development of Pol I inhibitory cancer therapeutic strategies. en
dc.format.extent 12
dc.language.iso eng
dc.relation.ispartof Journal of Medicinal Chemistry
dc.rights other
dc.rights.uri info:eu-repo/semantics/openAccess
dc.subject CANCER
dc.subject TRANSCRIPTION
dc.subject DISCOVERY
dc.subject NUCLEOLUS
dc.subject MECHANISM
dc.subject STRATEGY
dc.subject 317 Pharmacy
dc.title Design, Synthesis, and Structure-Activity Relationships of Pyridoquinazolinecarboxamides as RNA Polymerase I Inhibitors en
dc.type Article
dc.contributor.organization Faculty of Pharmacy
dc.contributor.organization Cancer Molecular biology and Therapeutics
dc.description.reviewstatus Peer reviewed
dc.relation.doi https://doi.org/10.1021/jm5004842
dc.relation.issn 0022-2623
dc.rights.accesslevel openAccess
dc.type.version publishedVersion

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