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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.. |
