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

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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

Title: Design, Synthesis, and Structure-Activity Relationships of Pyridoquinazolinecarboxamides as RNA Polymerase I Inhibitors
Author: Colis, Laureen; Ernst, Glen; Sanders, Sara; Liu, Hester; Sirajuddin, Paul; Peltonen, Karita; DePasquale, Michael; Barrow, James C.; Laiho, Marikki
Other contributor: University of Helsinki, Faculty of Pharmacy
University of Helsinki, Faculty of Pharmacy

Date: 2014-06-12
Language: eng
Number of pages: 12
Belongs to series: Journal of Medicinal Chemistry
ISSN: 0022-2623
DOI: https://doi.org/10.1021/jm5004842
URI: http://hdl.handle.net/10138/224460
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.
Subject: CANCER
TRANSCRIPTION
DISCOVERY
NUCLEOLUS
MECHANISM
STRATEGY
317 Pharmacy
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