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.

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.

Products

Cat. No.

Product Name

Description

Target

Research Area
HY-115519

(E/Z)-GO289

99.60%, CK2 Inhibitor

Casein Kinase

Cancer

Name
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