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Pre-clinical characterization of CX-4945, a potent and selective small molecule inhibitor of CK2 for the treatment of cancer

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Abstract

In this article we describe the preclinical characterization of 5-(3-chlorophenylamino) benzo[c][2,6]naphthyridine-8-carboxylic acid (CX-4945), the first orally available small molecule inhibitor of protein CK2 in clinical trials for cancer. CX-4945 was optimized as an ATP-competitive inhibitor of the CK2 holoenzyme (Ki = 0.38 nM). Iterative synthesis and screening of analogs, guided by molecular modeling, led to the discovery of orally available CX-4945. CK2 promotes signaling in the Akt pathway and CX-4945 suppresses the phosphorylation of Akt as well as other key downstream mediators of the pathway such as p21. CX-4945 induced apoptosis and caused cell cycle arrest in cancer cells in vitro. CX-4945 exhibited a dose-dependent antitumor activity in a xenograft model of PC3 prostate cancer model and was well tolerated. In vivo time-dependent reduction in the phosphorylation of the biomarker p21 at T145 was observed by immunohistochemistry. Inhibition of the newly validated CK2 target by CX-4945 represents a fresh therapeutic strategy for cancer.

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Abbreviations

IQA:

[5-oxo-5,6-dihydroindolo-(1,2-a)quinazolin-7-yl]acetic acid

PI3K:

Phosphatidylinositol-3-kinase

Akt:

v-akt murine thymoma viral oncogene homolog

PARP:

Poly(ADP-ribose) polymerase

LCMS:

Liquid chromatography mass spectrometry

NMR:

Nuclear magnetic resonance

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Authors and Affiliations

  1. Cylene Pharmaceuticals, 5820 Nancy Ridge Drive, Suite 200, San Diego, CA, 92121, USA

    Fabrice Pierre, Peter C. Chua, Sean E. O’Brien, Adam Siddiqui-Jain, Pauline Bourbon, Mustapha Haddach, Jerome Michaux, Johnny Nagasawa, Michael K. Schwaebe, Eric Stefan, Anne Vialettes, Jeffrey P. Whitten, Ta Kung Chen, Levan Darjania, Ryan Stansfield, Joshua Bliesath, Denis Drygin, Caroline Ho, May Omori, Chris Proffitt, Nicole Streiner, William G. Rice, David M. Ryckman & Kenna Anderes

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  1. Fabrice Pierre
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  2. Peter C. Chua
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  3. Sean E. O’Brien
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  4. Adam Siddiqui-Jain
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  5. Pauline Bourbon
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  7. Jerome Michaux
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  9. Michael K. Schwaebe
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  11. Anne Vialettes
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  12. Jeffrey P. Whitten
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  13. Ta Kung Chen
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  14. Levan Darjania
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  15. Ryan Stansfield
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  16. Joshua Bliesath
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  17. Denis Drygin
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  18. Caroline Ho
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  19. May Omori
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  20. Chris Proffitt
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  21. Nicole Streiner
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  22. William G. Rice
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  23. David M. Ryckman
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  24. Kenna Anderes
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Corresponding authors

Correspondence to Fabrice Pierre or Kenna Anderes.

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Pierre, F., Chua, P.C., O’Brien, S.E. et al. Pre-clinical characterization of CX-4945, a potent and selective small molecule inhibitor of CK2 for the treatment of cancer. Mol Cell Biochem 356, 37–43 (2011). https://doi.org/10.1007/s11010-011-0956-5

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  • DOI: https://doi.org/10.1007/s11010-011-0956-5

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