Cell-based screen identifies a new potent and highly selective CK2 inhibitor for modulation of circadian rhythms and cancer cell growth

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 & 6 others Kazuhiro Yagita, Masaaki Ikeda, Takayoshi Kinoshita, Steve A. Kay, Kenichiro Itami, Tsuyoshi Hirota

研究成果: Article

3 引用 (Scopus)

抄録

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-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.

元の言語English
記事番号eaau9060
ジャーナルScience Advances
5
発行部数1
DOI
出版物ステータスPublished - 2019 1 23

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Circadian Rhythm
Circadian Clocks
Phosphotransferases
Growth
Neoplasms
Phosphorylation
X-Rays
Proteins

ASJC Scopus subject areas

  • General

これを引用

Cell-based screen identifies a new potent and highly selective CK2 inhibitor for modulation of circadian rhythms and cancer cell growth. / Oshima, Tsuyoshi; Niwa, Yoshimi; Kuwata, Keiko; Srivastava, Ashutosh; Hyoda, Tomoko; Tsuchiya, Yoshiki; Kumagai, Megumi; Tsuyuguchi, Masato; Tamaru, Teruya; Sugiyama, Akiko; Ono, Natsuko; Zolboot, Norjin; Aikawa, Yoshiki; Oishi, Shunsuke; Nonami, Atsushi; Arai, Fumio; Hagihara, Shinya; Yamaguchi, Junichiro; Tama, Florence; Kunisaki, Yuya; Yagita, Kazuhiro; Ikeda, Masaaki; Kinoshita, Takayoshi; Kay, Steve A.; Itami, Kenichiro; Hirota, Tsuyoshi.

:: Science Advances, 巻 5, 番号 1, eaau9060, 23.01.2019.

研究成果: Article

Oshima, T, Niwa, Y, Kuwata, K, Srivastava, A, Hyoda, T, Tsuchiya, Y, Kumagai, M, Tsuyuguchi, M, Tamaru, T, Sugiyama, A, Ono, N, Zolboot, N, Aikawa, Y, Oishi, S, Nonami, A, Arai, F, Hagihara, S, Yamaguchi, J, Tama, F, Kunisaki, Y, Yagita, K, Ikeda, M, Kinoshita, T, Kay, SA, Itami, K & Hirota, T 2019, 'Cell-based screen identifies a new potent and highly selective CK2 inhibitor for modulation of circadian rhythms and cancer cell growth', Science Advances, 巻. 5, 番号 1, eaau9060. https://doi.org/10.1126/sciadv.aau9060
Oshima, Tsuyoshi ; Niwa, Yoshimi ; Kuwata, Keiko ; Srivastava, Ashutosh ; Hyoda, Tomoko ; Tsuchiya, Yoshiki ; Kumagai, Megumi ; Tsuyuguchi, Masato ; Tamaru, Teruya ; Sugiyama, Akiko ; Ono, Natsuko ; Zolboot, Norjin ; Aikawa, Yoshiki ; Oishi, Shunsuke ; Nonami, Atsushi ; Arai, Fumio ; Hagihara, Shinya ; Yamaguchi, Junichiro ; Tama, Florence ; Kunisaki, Yuya ; Yagita, Kazuhiro ; Ikeda, Masaaki ; Kinoshita, Takayoshi ; Kay, Steve A. ; Itami, Kenichiro ; Hirota, Tsuyoshi. / Cell-based screen identifies a new potent and highly selective CK2 inhibitor for modulation of circadian rhythms and cancer cell growth. :: Science Advances. 2019 ; 巻 5, 番号 1.
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abstract = "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-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.",
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AU - Oshima, Tsuyoshi

AU - Niwa, Yoshimi

AU - Kuwata, Keiko

AU - Srivastava, Ashutosh

AU - Hyoda, Tomoko

AU - Tsuchiya, Yoshiki

AU - Kumagai, Megumi

AU - Tsuyuguchi, Masato

AU - Tamaru, Teruya

AU - Sugiyama, Akiko

AU - Ono, Natsuko

AU - Zolboot, Norjin

AU - Aikawa, Yoshiki

AU - Oishi, Shunsuke

AU - Nonami, Atsushi

AU - Arai, Fumio

AU - Hagihara, Shinya

AU - Yamaguchi, Junichiro

AU - Tama, Florence

AU - Kunisaki, Yuya

AU - Yagita, Kazuhiro

AU - Ikeda, Masaaki

AU - Kinoshita, Takayoshi

AU - Kay, Steve A.

AU - Itami, Kenichiro

AU - Hirota, Tsuyoshi

PY - 2019/1/23

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