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.

1,8-cineole prevents UVB-induced skin carcinogenesis by targeting the aryl hydrocarbon receptor

“…In this study, we first observed that the natural monoterpenoid 1,8-cineole, which does not contain hydroxyl moieties, exhibits inhibitory effects against UVB-induced COX-2 expression by directly targeting AhR. DARTS is a method that can be used to identify the molecular targets of small molecules without chemical modification, and has been used to successfully identify the molecular targets of some anti-cancer drugs [ 38 , 39 ] and phytochemicals [ 40 , 41 ] without structural limits. However, DARTS has some limitations including drug binding affinity to its target as a limiting factor, the possibility of modifying protease susceptibility of non-target proteins following drug treatment, and low sensitivity with mass spectrometry [ 32 ].…”

Endogenous interaction profiling identifies DDX5 as an oncogenic coactivator of transcription factor Fra-1

“…Therefore, phosphorylated-DDX5 (p-DDX5) could be specifically targeted by anticancer molecule exhibiting strong growth inhibition, such as RX-5902 (Supinoxin), which binds directly to p-DDX5 in cancer cells to inhibit the interaction between p-DDX5 and b-catenin pathway resulting in blocking the b-catenin pathway and its downstream genes (e.g. c-Jun, c-Myc and cyclin D1) [287,319]. RX-5902 induced G2/M arrest and apoptosis in TNBC cells, and had additive effects of anti-tumor in vivo, currently, a phase 2 clinical trial in TNBC is ongoing (https://clinicaltrials.gov/ct2/show/NCT02003092) [320].…”

Dual role of the RNA helicase DDX5 in post-transcriptional regulation of myelin basic protein in oligodendrocytes

“…Interestingly, as a potential target in cancer therapy, DDX5 can be directly targeted by compounds already tested in humans, such as the antioxidant resveratrol (Taniguchi et al, 2016), the active component of green tea epigallocatechin gallate (ECGC) (Tanaka et al, 2011) or the synthetic drug Supinoxin/RX-5902 (Kost et al, 2015). It is conceivable that oligodendrocytespecific targeting of DDX5 could facilitate Mbp translation in vivo, aiding myelination or remyelination in the context of white matter disease.…”