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Design, synthesis, and structure-activity relationships of pyridoquinazolinecarboxamides as RNA polymerase I inhibitors.

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 Pol I 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 cytotoxicity. 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.
AuthorsLaureen Colis, Glen Ernst, Sara Sanders, Hester Liu, Paul Sirajuddin, Karita Peltonen, Michael DePasquale, James C Barrow, Marikki Laiho
JournalJournal of medicinal chemistry (J Med Chem) Vol. 57 Issue 11 Pg. 4950-61 (Jun 12 2014) ISSN: 1520-4804 [Electronic] United States
PMID24847734 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • Amides
  • Antineoplastic Agents
  • Pyridines
  • Quinazolines
  • RNA Polymerase I
Topics
  • Amides (chemical synthesis, chemistry, pharmacology)
  • Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
  • Cell Line, Tumor
  • Cell Nucleolus (metabolism)
  • Cell Survival (drug effects)
  • Drug Design
  • Drug Screening Assays, Antitumor
  • Humans
  • In Vitro Techniques
  • Microsomes, Liver (metabolism)
  • Pyridines (chemical synthesis, chemistry, pharmacology)
  • Quinazolines (chemical synthesis, chemistry, pharmacology)
  • RNA Polymerase I (antagonists & inhibitors)
  • Structure-Activity Relationship

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