title: Anticancer activity of CX-3543: a direct inhibitor of rRNA biogenesis.
abstract: Hallmark deregulated signaling in cancer cells drives excessive ribosome biogenesis within the nucleolus, which elicits unbridled cell growth and proliferation. The rate-limiting step of ribosome biogenesis is synthesis of rRNA (building blocks of ribosomes) by RNA Polymerase I (Pol I). Numerous kinase pathways and products of proto-oncogenes can up-regulate Pol I, whereas tumor suppressor proteins can inhibit rRNA synthesis. In tumorigenesis, activating mutations in certain cancer-associated kinases and loss-of-function mutations in tumor suppressors lead to deregulated signaling that stimulates Pol I transcription with resultant increases in ribosome biogenesis, protein synthesis, cell growth, and proliferation. Certain anticancer therapeutics, such as cisplatin and 5-fluorouracil, reportedly exert, at least partially, their activity through disruption of ribosome biogenesis, yet many prime targets for anticancer drugs within the ribosome synthetic machinery of the nucleolus remain largely unexploited. Herein, we describe CX-3543, a small molecule nucleolus-targeting agent that selectively disrupts nucleolin/rDNA G-quadruplex complexes in the nucleolus, thereby inhibiting Pol I transcription and inducing apoptosis in cancer cells. CX-3543 is the first G-quadruplex interactive agent to enter human clinical trials, and it is currently under evaluation against carcinoid/neuroendocrine tumors in a phase II clinical trial.
authors.affiliation: Cylene Pharmaceuticals, Inc., San Diego, CA 92121, USA.
authors.forename: Denis
authors.initials: D
authors.lastname: Drygin
authors.forename: Adam
authors.initials: A
authors.lastname: Siddiqui-Jain
authors.forename: Sean
authors.initials: S
authors.lastname: O'Brien
authors.forename: Michael
authors.initials: M
authors.lastname: Schwaebe
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: Chris
authors.initials: C
authors.lastname: Proffitt
authors.forename: Katy
authors.initials: K
authors.lastname: Trent
authors.forename: Jeffrey P
authors.initials: JP
authors.lastname: Whitten
authors.forename: John K C
authors.initials: JK
authors.lastname: Lim
authors.forename: Daniel
authors.initials: D
authors.lastname: Von Hoff
authors.forename: Kenna
authors.initials: K
authors.lastname: Anderes
authors.forename: William G
authors.initials: WG
authors.lastname: Rice
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D048588:Benzoxazines / Q000493:pharmacokinetics / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002466:Cell Nucleolus / Q000187:drug effects / Q000378:metabolism; D004256:DNA Polymerase I / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D005260:Female; D054856:G-Quadruplexes / Q000187:drug effects; D018922:HL-60 Cells; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016513:Mice, SCID; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D010750:Phosphoproteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015363:Quinolones / Q000493:pharmacokinetics / Q000494:pharmacology*; D012335:RNA, Ribosomal / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D016601:RNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D016615:Telomere / Q000187:drug effects; D014158:Transcription, Genetic / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D000097796:Nucleolin
chemical_list: D048588:Benzoxazines; D004256:DNA Polymerase I; D004264:DNA Topoisomerases, Type I; D004250:DNA Topoisomerases, Type II; D010750:Phosphoproteins; D015363:Quinolones; D012335:RNA, Ribosomal; D016601:RNA-Binding Proteins; D000097796:Nucleolin; C545184:CX 3543