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
  • 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.
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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