title: Targeting RNA polymerase I with an oral small molecule CX-5461 inhibits ribosomal RNA synthesis and solid tumor growth.
abstract: Deregulated ribosomal RNA synthesis is associated with uncontrolled cancer cell proliferation. RNA polymerase (Pol) I, the multiprotein complex that synthesizes rRNA, is activated widely in cancer. Thus, selective inhibitors of Pol I may offer a general therapeutic strategy to block cancer cell proliferation. Coupling medicinal chemistry efforts to tandem cell- and molecular-based screening led to the design of CX-5461, a potent small-molecule inhibitor of rRNA synthesis in cancer cells. CX-5461 selectively inhibits Pol I-driven transcription relative to Pol II-driven transcription, DNA replication, and protein translation. Molecular studies demonstrate that CX-5461 inhibits the initiation stage of rRNA synthesis and induces both senescence and autophagy, but not apoptosis, through a p53-independent process in solid tumor cell lines. CX-5461 is orally bioavailable and demonstrates in vivo antitumor activity against human solid tumors in murine xenograft models. Our findings position CX-5461 for investigational clinical trials as a potent, selective, and orally administered agent for cancer treatment.
authors.affiliation: Cylene Pharmaceuticals, Inc., San Diego, California, USA.
authors.forename: Denis
authors.initials: D
authors.lastname: Drygin
authors.forename: Amy
authors.initials: A
authors.lastname: Lin
authors.forename: Josh
authors.initials: J
authors.lastname: Bliesath
authors.forename: Caroline B
authors.initials: CB
authors.lastname: Ho
authors.forename: Sean E
authors.initials: SE
authors.lastname: O'Brien
authors.forename: Chris
authors.initials: C
authors.lastname: Proffitt
authors.forename: Mayuko
authors.initials: M
authors.lastname: Omori
authors.forename: Mustapha
authors.initials: M
authors.lastname: Haddach
authors.forename: Michael K
authors.initials: MK
authors.lastname: Schwaebe
authors.forename: Adam
authors.initials: A
authors.lastname: Siddiqui-Jain
authors.forename: Nicole
authors.initials: N
authors.lastname: Streiner
authors.forename: Jaclyn E
authors.initials: JE
authors.lastname: Quin
authors.forename: Elaine
authors.initials: E
authors.lastname: Sanij
authors.forename: Megan J
authors.initials: MJ
authors.lastname: Bywater
authors.forename: Ross D
authors.initials: RD
authors.lastname: Hannan
authors.forename: David
authors.initials: D
authors.lastname: Ryckman
authors.forename: Kenna
authors.initials: K
authors.lastname: Anderes
authors.forename: William G
authors.initials: WG
authors.lastname: Rice
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D052160:Benzothiazoles / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D049109:Cell Proliferation / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D045325:HCT116 Cells; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D058990:Molecular Targeted Therapy / Q000379:methods; D009287:Naphthyridines / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D012318:RNA Polymerase I / Q000037:antagonists & inhibitors* / Q000235:genetics; D012335:RNA, Ribosomal / Q000096:biosynthesis*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D052160:Benzothiazoles; C557717:CX 5461; D004791:Enzyme Inhibitors; D009287:Naphthyridines; D012335:RNA, Ribosomal; D012318:RNA Polymerase I