title: 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.
authors: Rexahn Pharmaceuticals, Inc., Rockville, Maryland, 20850.
authors: Gina Chun
authors: GC
authors: Kost
authors: Rexahn Pharmaceuticals, Inc., Rockville, Maryland, 20850.
authors: Mi Young
authors: MY
authors: Yang
authors: Department of Biology, Georgia State University, Atlanta, Georgia, 30303.
authors: Liangwei
authors: L
authors: Li
authors: Department of Biology, Georgia State University, Atlanta, Georgia, 30303.
authors: Yinwei
authors: Y
authors: Zhang
authors: Department of Biology, Georgia State University, Atlanta, Georgia, 30303.
authors: Chia-Yi
authors: CY
authors: Liu
authors: Rexahn Pharmaceuticals, Inc., Rockville, Maryland, 20850.
authors: Deog Joong
authors: DJ
authors: Kim
authors: Rexahn Pharmaceuticals, Inc., Rockville, Maryland, 20850.
authors: Chang-Ho
authors: CH
authors: Ahn
authors: Rexahn Pharmaceuticals, Inc., Rockville, Maryland, 20850.
authors: Young Bok
authors: YB
authors: Lee
authors: Department of Biology, Georgia State University, Atlanta, Georgia, 30303.
authors: Zhi-Ren
authors: ZR
authors: Liu
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001665:Binding Sites / Q000187:drug effects; D045744:Cell Line, Tumor; D053487:DEAD-box RNA Helicases / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D010766:Phosphorylation; D010879:Piperazines / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D011810:Quinoxalines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D010879:Piperazines; D011810:Quinoxalines; C000606305:RX-5902; D051176:beta Catenin; D053487:DEAD-box RNA Helicases
keywords: ANTI-CANCER; PHOSPHO-p68; RX-5902; p68 RNA HELICASE