title: 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.affiliation: Cylene Pharmaceuticals , 5820 Nancy Ridge Drive, Suite 200, San Diego, California 92121, United States.
authors.forename: Mustapha
authors.initials: M
authors.lastname: Haddach
authors.affiliation: Cylene Pharmaceuticals , 5820 Nancy Ridge Drive, Suite 200, San Diego, California 92121, United States.
authors.forename: Michael K
authors.initials: MK
authors.lastname: Schwaebe
authors.affiliation: Cylene Pharmaceuticals , 5820 Nancy Ridge Drive, Suite 200, San Diego, California 92121, United States.
authors.forename: Jerome
authors.initials: J
authors.lastname: Michaux
authors.affiliation: Cylene Pharmaceuticals , 5820 Nancy Ridge Drive, Suite 200, San Diego, California 92121, United States.
authors.forename: Johnny
authors.initials: J
authors.lastname: Nagasawa
authors.affiliation: Cylene Pharmaceuticals , 5820 Nancy Ridge Drive, Suite 200, San Diego, California 92121, United States.
authors.forename: Sean E
authors.initials: SE
authors.lastname: O'Brien
authors.affiliation: Cylene Pharmaceuticals , 5820 Nancy Ridge Drive, Suite 200, San Diego, California 92121, United States.
authors.forename: Jeffrey P
authors.initials: JP
authors.lastname: Whitten
authors.affiliation: Cylene Pharmaceuticals , 5820 Nancy Ridge Drive, Suite 200, San Diego, California 92121, United States.
authors.forename: Fabrice
authors.initials: F
authors.lastname: Pierre
authors.affiliation: Cylene Pharmaceuticals , 5820 Nancy Ridge Drive, Suite 200, San Diego, California 92121, United States.
authors.forename: Pauline
authors.initials: P
authors.lastname: Kerdoncuff
authors.affiliation: Cylene Pharmaceuticals , 5820 Nancy Ridge Drive, Suite 200, San Diego, California 92121, United States.
authors.forename: Levan
authors.initials: L
authors.lastname: Darjania
authors.affiliation: Cylene Pharmaceuticals , 5820 Nancy Ridge Drive, Suite 200, San Diego, California 92121, United States.
authors.forename: Ryan
authors.initials: R
authors.lastname: Stansfield
authors.affiliation: Cylene Pharmaceuticals , 5820 Nancy Ridge Drive, Suite 200, San Diego, California 92121, United States.
authors.forename: Denis
authors.initials: D
authors.lastname: Drygin
authors.affiliation: Cylene Pharmaceuticals , 5820 Nancy Ridge Drive, Suite 200, San Diego, California 92121, United States.
authors.forename: Kenna
authors.initials: K
authors.lastname: Anderes
authors.affiliation: Cylene Pharmaceuticals , 5820 Nancy Ridge Drive, Suite 200, San Diego, California 92121, United States.
authors.forename: Chris
authors.initials: C
authors.lastname: Proffitt
authors.affiliation: Cylene Pharmaceuticals , 5820 Nancy Ridge Drive, Suite 200, San Diego, California 92121, United States.
authors.forename: Josh
authors.initials: J
authors.lastname: Bliesath
authors.affiliation: Cylene Pharmaceuticals , 5820 Nancy Ridge Drive, Suite 200, San Diego, California 92121, United States.
authors.forename: Adam
authors.initials: A
authors.lastname: Siddiqui-Jain
authors.affiliation: Cylene Pharmaceuticals , 5820 Nancy Ridge Drive, Suite 200, San Diego, California 92121, United States.
authors.forename: May
authors.initials: M
authors.lastname: Omori
authors.affiliation: Cylene Pharmaceuticals , 5820 Nancy Ridge Drive, Suite 200, San Diego, California 92121, United States.
authors.forename: Nanni
authors.initials: N
authors.lastname: Huser
authors.affiliation: Cylene Pharmaceuticals , 5820 Nancy Ridge Drive, Suite 200, San Diego, California 92121, United States.
authors.forename: William G
authors.initials: WG
authors.lastname: Rice
authors.affiliation: Cylene Pharmaceuticals , 5820 Nancy Ridge Drive, Suite 200, San Diego, California 92121, United States.
authors.forename: David M
authors.initials: DM
authors.lastname: Ryckman
keywords: CX-5461; RNA polymerase I; p53; rRNA