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A Novel Anti-Cancer Agent, 1-(3,5-Dimethoxyphenyl)-4-[(6-Fluoro-2-Methoxyquinoxalin-3-yl)Aminocarbonyl] Piperazine (RX-5902), Interferes With β-Catenin Function Through Y593 Phospho-p68 RNA Helicase.

Abstract
1-(3,5-Dimethoxyphenyl)-4-[(6-fluoro-2-methoxyquinoxalin-3-yl)aminocarbonyl] piperazine (RX-5902) exhibits strong growth inhibition in various human cancer cell lines with IC50 values ranging between 10 and 20 nM. In this study, we demonstrate that p68 RNA helicase is a cellular target of RX-5902 by the drug affinity responsive target stability (DARTS) method, and confirmed the direct binding of (3) H-labeled RX-5902 to Y593 phospho-p68 RNA helicase. We further demonstrated RX-5902 inhibited the β-catenin dependent ATPase activity of p68 RNA helicase in an in vitro system. Furthermore, we showed that treatment of cancer cells with RX-5902 resulted in the downregulation of the expression of certain genes, which are known to be regulated by the β-catenin pathway, such as c-Myc, cyclin D1 and p-c-Jun. Therefore, our study indicates that the inhibition of Y593 phospho-p68 helicase - β-catenin interaction by direct binding of RX-5902 to Y593 phospho-p68 RNA helicase may contribute to the anti-cancer activity of this compound.
AuthorsGina Chun Kost, Mi Young Yang, Liangwei Li, Yinwei Zhang, Chia-Yi Liu, Deog Joong Kim, Chang-Ho Ahn, Young Bok Lee, Zhi-Ren Liu
JournalJournal of cellular biochemistry (J Cell Biochem) Vol. 116 Issue 8 Pg. 1595-601 (Aug 2015) ISSN: 1097-4644 [Electronic] United States
PMID25649741 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Copyright© 2015 Wiley Periodicals, Inc.
Chemical References
  • Antineoplastic Agents
  • Piperazines
  • Quinoxalines
  • RX-5902
  • beta Catenin
  • DEAD-box RNA Helicases
Topics
  • Antineoplastic Agents (pharmacology)
  • Binding Sites (drug effects)
  • Cell Line, Tumor
  • DEAD-box RNA Helicases (chemistry, metabolism)
  • Humans
  • Neoplasms (drug therapy, metabolism)
  • Phosphorylation
  • Piperazines (pharmacology)
  • Protein Binding (drug effects)
  • Quinoxalines (pharmacology)
  • Signal Transduction (drug effects)
  • beta Catenin (metabolism)

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