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

Laureen Colis, Glen Ernst, Sara Sanders, Hester Liu, Paul Sirajuddin, Karita Peltonen, Michael Depasquale, James C. Barrow, Marikki Laiho

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)4950-4961
Number of pages12
JournalJournal of medicinal chemistry
Volume57
Issue number11
DOIs
StatePublished - Jun 12 2014

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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