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

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

  • Sci Adv. 2019 Jan 23;5(1):eaau9060. doi: 10.1126/sciadv.aau9060.
Tsuyoshi Oshima 1 2,  Yoshimi Niwa 1,  Keiko Kuwata 1,  Ashutosh Srivastava 1,  Tomoko Hyoda 3,  Yoshiki Tsuchiya 4,  Megumi Kumagai 5,  Masato Tsuyuguchi 6,  Teruya Tamaru 7,  Akiko Sugiyama 1,  Natsuko Ono 1,  Norjin Zolboot 1,  Yoshiki Aikawa 1,  Shunsuke Oishi 1,  Atsushi Nonami 8,  Fumio Arai 9,  Shinya Hagihara 1 2 10,  Junichiro Yamaguchi 11,  Florence Tama 1 12,  Yuya Kunisaki 9,  Kazuhiro Yagita 4,  Masaaki Ikeda 5,  Takayoshi Kinoshita 6,  Steve A Kay 1 13,  Kenichiro Itami 1 2 14,  Tsuyoshi Hirota 1 10
Affiliations

Affiliations

  • 1 Institute of Transformative Bio-Molecules, Nagoya University, Nagoya 464-8601, Japan.
  • 2 Department of Chemistry, Graduate School of Science, Nagoya University, Nagoya 464-8601, Japan.
  • 3 Department of Health Sciences, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
  • 4 Department of Physiology and Systems Bioscience, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan.
  • 5 Department of Physiology, Faculty of Medicine, Saitama Medical University, Saitama 350-0495, Japan.
  • 6 Graduate School of Science, Osaka Prefecture University, Osaka 599-8531, Japan.
  • 7 Department of Physiology and Advanced Research Center for Medical Science, Toho University School of Medicine, Tokyo 143-8540, Japan.
  • 8 Center for Advanced Medical Innovation, Kyushu University, Fukuoka 812-8582, Japan.
  • 9 Department of Stem Cell Biology and Medicine/Cancer Stem Cell Research, Kyushu University Graduate School of Medical Sciences, Fukuoka 812-8582, Japan.
  • 10 PRESTO, JST, Nagoya 464-8601, Japan.
  • 11 Department of Applied Chemistry, Waseda University, Tokyo 169-8555, Japan.
  • 12 Department of Physics, Graduate School of Science, Nagoya University, Nagoya 464-8601, Japan, and RIKEN Center for Computational Science, Kobe 650-0047, Japan.
  • 13 Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA.
  • 14 ERATO Itami Molecular Nanocarbon Project, JST, Nagoya 464-8601, Japan.
PMID: 30746467 DOI: 10.1126/sciadv.aau9060
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 CK2α-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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