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

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Abstract

We discovered a new CK2 inhibitor and revealed its mechanism of action, connecting the circadian clock and cancer regulation.

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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Most cited references 52

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A small molecule-kinase interaction map for clinical kinase inhibitors.

Miles Fabian, William Biggs, Daniel Treiber … (2005)

Kinase inhibitors show great promise as a new class of therapeutics. Here we describe an efficient way to determine kinase inhibitor specificity by measuring binding of small molecules to the ATP site of kinases. We have profiled 20 kinase inhibitors, including 16 that are approved drugs or in clinical development, against a panel of 119 protein kinases. We find that specificity varies widely and is not strongly correlated with chemical structure or the identity of the intended target. Many novel interactions were identified, including tight binding of the p38 inhibitor BIRB-796 to an imatinib-resistant variant of the ABL kinase, and binding of imatinib to the SRC-family kinase LCK. We also show that mutations in the epidermal growth factor receptor (EGFR) found in gefitinib-responsive patients do not affect the binding affinity of gefitinib or erlotinib. Our results represent a systematic small molecule-protein interaction map for clinical compounds across a large number of related proteins.

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Posttranslational mechanisms regulate the mammalian circadian clock.

C. Lee, J P Etchegaray, F. Cagampang … (2001)

We have examined posttranslational regulation of clock proteins in mouse liver in vivo. The mouse PERIOD proteins (mPER1 and mPER2), CLOCK, and BMAL1 undergo robust circadian changes in phosphorylation. These proteins, the cryptochromes (mCRY1 and mCRY2), and casein kinase I epsilon (CKIepsilon) form multimeric complexes that are bound to DNA during negative transcriptional feedback. CLOCK:BMAL1 heterodimers remain bound to DNA over the circadian cycle. The temporal increase in mPER abundance controls the negative feedback interactions. Analysis of clock proteins in mCRY-deficient mice shows that the mCRYs are necessary for stabilizing phosphorylated mPER2 and for the nuclear accumulation of mPER1, mPER2, and CKIepsilon. We also provide in vivo evidence that casein kinase I delta is a second clock relevant kinase.

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CX-4945, an orally bioavailable selective inhibitor of protein kinase CK2, inhibits prosurvival and angiogenic signaling and exhibits antitumor efficacy.

Adam Siddiqui-Jain, Denis Drygin, Nicole Streiner … (2010)

Malignant transformation and maintenance of the malignant phenotype depends on oncogenic and non-oncogenic proteins that are essential to mediate oncogene signaling and to support the altered physiologic demands induced by transformation. Protein kinase CK2 supports key prosurvival signaling pathways and represents a prototypical non-oncogene. In this study, we describe CX-4945, a potent and selective orally bioavailable small molecule inhibitor of CK2. The antiproliferative activity of CX-4945 against cancer cells correlated with expression levels of the CK2α catalytic subunit. Attenuation of PI3K/Akt signaling by CX-4945 was evidenced by dephosphorylation of Akt on the CK2-specific S129 site and the canonical S473 and T308 regulatory sites. CX-4945 caused cell-cycle arrest and selectively induced apoptosis in cancer cells relative to normal cells. In models of angiogenesis, CX-4945 inhibited human umbilical vein endothelial cell migration, tube formation, and blocked CK2-dependent hypoxia-induced factor 1 alpha (HIF-1α) transcription in cancer cells. When administered orally in murine xenograft models, CX-4945 was well tolerated and demonstrated robust antitumor activity with concomitant reductions of the mechanism-based biomarker phospho-p21 (T145). The observed antiproliferative and anti-angiogenic responses to CX-4945 in tumor cells and endothelial cells collectively illustrate that this compound exerts its antitumor effects through inhibition of CK2-dependent signaling in multiple pathways. Finally, CX-4945 is the first orally bioavailable small molecule inhibitor of CK2 to advance into human clinical trials, thereby paving the way for an entirely new class of targeted treatment for cancer. ©2010 AACR.

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Author and article information

Journal

Journal ID (nlm-ta): Sci Adv

Journal ID (iso-abbrev): Sci Adv

Journal ID (publisher-id): SciAdv

Journal ID (hwp): advances

Title: Science Advances

Publisher: American Association for the Advancement of Science

ISSN (Electronic): 2375-2548

Publication date Collection: January 2019

Publication date (Electronic): 23 January 2019

Volume: 5

Issue: 1

Electronic Location Identifier: eaau9060

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.

Author notes

[*]

These authors contributed equally to this work.

[† ]Corresponding author. Email: thirota@ 123456itbm.nagoya-u.ac.jp (T.H.); itami@ 123456chem.nagoya-u.ac.jp (K.I.)

Author information

Tsuyoshi Oshima http://orcid.org/0000-0002-4751-9948

Yoshimi Niwa http://orcid.org/0000-0001-6379-6729

Ashutosh Srivastava http://orcid.org/0000-0001-9820-720X

Tomoko Hyoda http://orcid.org/0000-0002-2310-7965

Megumi Kumagai http://orcid.org/0000-0003-2409-5836

Norjin Zolboot http://orcid.org/0000-0002-1473-7316

Fumio Arai http://orcid.org/0000-0003-1936-4907

Shinya Hagihara http://orcid.org/0000-0003-0348-7873

Junichiro Yamaguchi http://orcid.org/0000-0002-3896-5882

Florence Tama http://orcid.org/0000-0003-2021-5618

Masaaki Ikeda http://orcid.org/0000-0002-3469-6312

Steve A. Kay http://orcid.org/0000-0002-0402-2878

Kenichiro Itami http://orcid.org/0000-0001-5227-7894

Tsuyoshi Hirota http://orcid.org/0000-0003-4876-3608

Article

Publisher ID: aau9060

DOI: 10.1126/sciadv.aau9060

PMC ID: 6357737

PubMed ID: 30746467

SO-VID: b3eed25f-b588-45be-9d5a-c3842ff09df6

Copyright © Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license, which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited.

History

Date received : 26 July 2018

Date accepted : 11 December 2018