||Tsuyoshi Oshima, Yoshimi Niwa, Keiko Kuwata, Ashutosh Srivastava, Tomoko Hyoda, Yoshiki Tsuchiya, Megumi Kumagai, Masato Tsuyuguchi, Teruya Tamaru, Akiko Sugiyama, Natsuko Ono, Norjin Zolboot, Yoshiki Aikawa, Shunsuke Oishi, Atsushi Nonami, Fumio Arai, Shinya Hagihara, Junichiro Yamaguchi, Florence Tama, Yuya Kunisaki, Kazuhiro Yagita, Masaaki Ikeda, Takayoshi Kinoshita, Steve A. Kay, Kenichiro Itami, and Tsuyoshi Hirota, Cell-based screen identifies a new potent and highly selective CK2 inhibitor for modulation of circadian rhythms and cancer cell growth., Science Advances, 10.1126, 5, 1, eaau9060, 2019.01, Compounds targeting the circadian clock have been identified as potential treatments for clock-related diseases, including cancer. Our cell-based phenotypic screen revealed uncharacterized clock-modulating compounds. Through affinity-based target deconvolution, we identified GO289, which strongly lengthened circadian period, as a potent and selective inhibitor of CK2. Phosphoproteomics identified multiple phosphorylation sites inhibited by GO289 on clock proteins, including PER2 S693. Furthermore, GO289 exhibited cell type-dependent inhibition of cancer cell growth that correlated with cellular clock function. The x-ray crystal structure of the CK2 alpha-GO289 complex revealed critical interactions between GO289 and CK2-specific residues and no direct interaction of GO289 with the hinge region that is highly conserved among kinases. The discovery of GO289 provides a direct link between the circadian clock and cancer regulation and reveals unique design principles underlying kinase selectivity..
||Tomoko Hyoda, Takayuki Tsujioka, Takako Nakahara, Shinichiro Suemori, Shuichiro Okamoto, Mikio Kataoka, Kaoru Tohyama, Rigosertib induces cell death of an MDS-derived cell line by DNA damage-induced G2/M arrest., Cancer Science, 106, 3, 287-293, 2015.03, A multi-kinase inhibitor, rigosertib (ON 01910.Na) has recently been highlighted as a novel type of anti-cancer agent for the treatment of the myelodysplastic syndromes (MDS), but its action mechanisms remain to be clarified. We investigated the invitro effects of rigosertib on an MDS-derived cell line MDS-L and a myeloid leukemia cell line HL-60. Rigosertib suppressed the proliferation of both HL-60 and MDS-L cells and induced apoptosis by inhibition of the PI3 kinase/Akt pathway. As the effects on cell cycle, rigosertib treatment promoted the phosphorylation of histone H2AX and led to the DNA damage-induced G2/M arrest. In addition, an immunofluorescence staining study demonstrated the abnormal localization of aurora A kinase, suggesting that rigosertib causes perturbation of spindle assembly and deregulated mitotic patterns towards cell cycle arrest and apoptosis. We also found that rigosertib exerted growth inhibitory effects on two lymphoid cell lines, Jurkat and Ramos. We further examined the molecular pathways influenced by rigosertib from the gene expression profiling data of MDS-L cells and found a possible involvement of rigosertib treatment in the upregulation of the genes related to microtubule kinetics and the downregulation of the mRNA degradation system. The gene set enrichment analysis showed the suppression of nonsense-mediated mRNA decay (NMD) as the most significantly affected gene set. These data provide a new aspect and a potential utility of rigosertib for the treatment of refractory hematopoietic malignancies..
||Tomoe Iio, Misako Shibakura, Kanayo Yokota, Michinori Aoe, Tomoko Hyoda, Ryoko Shinohata, Arihiko Kanehiro, Mitsune Tanimoto, Mikio Kataoka, Lavender essential oil inhalation suppresses allergic airway inflammation and mucous cell hyperplasia in a murine model of asthma., Life science, 108, 2, 109-115, 2014.07.