Anticancer Activity of CX-3543: A Direct Inhibitor of rRNA Biogenesis

Drygin, Denis; Siddiqui‐Jain, Adam; O’Brien, Sean; Schwaebe, Michael K.; Lin, Amy; Bliesath, Josh; Ho, Caroline B.; Proffitt, Chris; Trent, Katy; Whitten, Jeffrey P.; Lim, Jeehee; Hoff, Daniel D. Von; Anderes, Kenna; Rice, William G.

doi:10.1158/0008-5472.can-09-1304

Cited by 487 publications

(465 citation statements)

References 55 publications

(56 reference statements)

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“…Cells were treated with 2 mmol/L of CX-5461 for 1 hour and chromatin immunoprecipitation (ChIP) assay was performed as previously described (11,12).…”

Section: Chromatin Immunoprecipitationmentioning

confidence: 99%

Targeting RNA Polymerase I with an Oral Small Molecule CX-5461 Inhibits Ribosomal RNA Synthesis and Solid Tumor Growth

et al. 2011

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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.

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“…Cells were treated with 2 mmol/L of CX-5461 for 1 hour and chromatin immunoprecipitation (ChIP) assay was performed as previously described (11,12).…”

Section: Chromatin Immunoprecipitationmentioning

confidence: 99%

Targeting RNA Polymerase I with an Oral Small Molecule CX-5461 Inhibits Ribosomal RNA Synthesis and Solid Tumor Growth

et al. 2011

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“…57 These regions, as well as the 28S region, were shown to be enriched in G-quadruplex sequences in the nontemplate strand. 58 Consistently with its role as a Gquadruplex-binding protein, NPM1 was later shown to bind these regions both in vitro and in vivo. 34 This activity was completely lost by the unstructured leukemic mutant A C-terminal domain.…”

Section: G-quadruplex Binding and Nucleolar Localizationmentioning

confidence: 75%

“…34 However, and unexpectedly, OCI-AML3 cells, which bear heterozygous NPM1 mutation A, proved more resistant to treatment than the control OCI-AML2 cells, bearing wild-type NPM1 at both alleles. 34 Even though the reasons for such increased resistance are still under investigation, it should be emphasized that G-quadruplex ligands may not be ideal for this purpose because, together with NPM1, they may also displace from nucleoli other proteins, including nucleolin, 58 thus proving toxic to normal cells too. 34 An ideal ligand, in order to be specific for NPM1, should target the surface of NPM1 that interacts with G-quadruplexes, rather than the G- (A) As wild-type NPM1 oligomerizes with mutated NPM1 and is thus translocated to the cytosol, only a small fraction of the protein is retained in nucleoli.…”

Section: Posttranslational Modifications and Molecules That Bind Npm1mentioning

confidence: 99%

Nucleophosmin mutations in acute myeloid leukemia: A tale of protein unfolding and mislocalization

Federici

Falini

2013

Protein Science

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Nucleophosmin (NPM1) is an abundant, ubiquitously expressed protein mainly localized at nucleoli but continuously shuttling between nucleus and cytoplasm. NPM1 plays a role in several cellular functions, including ribosome biogenesis and export, centrosome duplication, chromatin remodeling, DNA repair, and response to stress stimuli. Much of the interest in this protein arises from its relevance in human malignancies. NPM1 is frequently overexpressed in solid tumors and is the target of several chromosomal translocations in hematologic neoplasms. Notably, NPM1 has been characterized as the most frequently mutated gene in acute myeloid leukemia (AML). Mutations alter the C-terminal DNAbinding domain of the protein and result in its aberrant nuclear export and stable cytosolic localization. In this review, we focus on the leukemia-associated NPM1 C-terminal domain and describe its structure, function, and the effect exerted by leukemic mutations. Finally, we discuss the possibility to target NPM1 for the treatment of cancer and, in particular, of AML patients with mutated NPM1 gene.

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“…The association of RHPS4 and a PARP1 inhibitor, the latter currently in clinical trials, was shown to act de concert in the treatment of human colorectal adenocarcinoma mice xenografts, demonstrating the clinical relevance of a telomeric G-quadruplex-based therapy. Recently, the drug quarfloxin entered Phase II clinical trials for the treatment of carcinoid/neuroendocrine tumors [18]. In this study, the authors suggested that quarfloxin accumulates in the nucleolus and selectively binds to rDNA-containing G-quadruplexes.…”

Section: Biological Evidence Of Functional G-quadruplex Dnamentioning

confidence: 98%