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Design, synthesis, and structure-activity relationships of pyridoquinazolinecarboxamides as RNA polymerase I inhibitors.
J Med Chem 2014; 57(11):4950-61JM

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.

Authors+Show Affiliations

Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine , 1550 Orleans Street, Baltimore, Maryland 21287, United States.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24847734

Citation

Colis, Laureen, et al. "Design, Synthesis, and Structure-activity Relationships of Pyridoquinazolinecarboxamides as RNA Polymerase I Inhibitors." Journal of Medicinal Chemistry, vol. 57, no. 11, 2014, pp. 4950-61.
Colis L, Ernst G, Sanders S, et al. Design, synthesis, and structure-activity relationships of pyridoquinazolinecarboxamides as RNA polymerase I inhibitors. J Med Chem. 2014;57(11):4950-61.
Colis, L., Ernst, G., Sanders, S., Liu, H., Sirajuddin, P., Peltonen, K., ... Laiho, M. (2014). Design, synthesis, and structure-activity relationships of pyridoquinazolinecarboxamides as RNA polymerase I inhibitors. Journal of Medicinal Chemistry, 57(11), pp. 4950-61. doi:10.1021/jm5004842.
Colis L, et al. Design, Synthesis, and Structure-activity Relationships of Pyridoquinazolinecarboxamides as RNA Polymerase I Inhibitors. J Med Chem. 2014 Jun 12;57(11):4950-61. PubMed PMID: 24847734.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Design, synthesis, and structure-activity relationships of pyridoquinazolinecarboxamides as RNA polymerase I inhibitors. AU - Colis,Laureen, AU - Ernst,Glen, AU - Sanders,Sara, AU - Liu,Hester, AU - Sirajuddin,Paul, AU - Peltonen,Karita, AU - DePasquale,Michael, AU - Barrow,James C, AU - Laiho,Marikki, Y1 - 2014/05/30/ PY - 2014/5/23/entrez PY - 2014/5/23/pubmed PY - 2014/8/21/medline SP - 4950 EP - 61 JF - Journal of medicinal chemistry JO - J. Med. Chem. VL - 57 IS - 11 N2 - 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. SN - 1520-4804 UR - https://www.unboundmedicine.com/medline/citation/24847734/Design_synthesis_and_structure_activity_relationships_of_pyridoquinazolinecarboxamides_as_RNA_polymerase_I_inhibitors_ L2 - https://dx.doi.org/10.1021/jm5004842 DB - PRIME DP - Unbound Medicine ER -