Discovery of CX-5461, the First Direct and Selective Inhibitor of RNA Polymerase I, for Cancer Therapeutics.

Abstract

Accelerated proliferation of solid tumor and hematologic cancer cells is linked to accelerated transcription of rDNA by the RNA polymerase I (Pol I) enzyme to produce elevated levels of rRNA (rRNA). Indeed, upregulation of Pol I, frequently caused by mutational alterations among tumor suppressors and oncogenes, is required for maintenance of the cancer phenotype and forms the basis for seeking selective inhibitors of Pol I as anticancer therapeutics. 2-(4-Methyl-[1,4]diazepan-1-yl)-5-oxo-5H-7-thia-1,11b-diaza-benzo[c]fluorene-6-carboxylic acid (5-methyl-pyrazin-2-ylmethyl)-amide (CX-5461, 7c) has been identified as the first potent, selective, and orally bioavailable inhibitor of RNA Pol I transcription with in vivo activity in tumor growth efficacy models. The preclinical data support the development of CX-5461 as an anticancer drug with potential for activity in several types of cancer.

• Authors: Mustapha Haddach, Michael K Schwaebe, Jerome Michaux, Johnny Nagasawa, Sean E O'Brien, Jeffrey P Whitten, Fabrice Pierre, Pauline Kerdoncuff, Levan Darjania, Ryan Stansfield, Denis Drygin, Kenna Anderes, Chris Proffitt, Josh Bliesath, Adam Siddiqui-Jain, May Omori, Nanni Huser, William G Rice, David M Ryckman
• Journal: ACS medicinal chemistry letters (ACS Med Chem Lett) Vol. 3 Issue 7 Pg. 602-6 (Jul 12 2012) ISSN: 1948-5875 [Print] United States
• PMID: 24900516 (Publication Type: Journal Article)