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

  • 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
Article

DOI: 10.1007/s11010-011-0956-5

Cite this article as:
Pierre, F., Chua, P.C., O’Brien, S.E. et al. Mol Cell Biochem (2011) 356: 37. doi:10.1007/s11010-011-0956-5

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.

Keywords

CK2CancerProstate cancerNon-oncogeneOncologyKinase inhibitor

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

Copyright information

© Springer Science+Business Media, LLC. 2011

Authors and Affiliations

  • Fabrice Pierre
    • 1
  • Peter C. Chua
    • 1
  • Sean E. O’Brien
    • 1
  • Adam Siddiqui-Jain
    • 1
  • Pauline Bourbon
    • 1
  • Mustapha Haddach
    • 1
  • Jerome Michaux
    • 1
  • Johnny Nagasawa
    • 1
  • Michael K. Schwaebe
    • 1
  • Eric Stefan
    • 1
  • Anne Vialettes
    • 1
  • Jeffrey P. Whitten
    • 1
  • Ta Kung Chen
    • 1
  • Levan Darjania
    • 1
  • Ryan Stansfield
    • 1
  • Joshua Bliesath
    • 1
  • Denis Drygin
    • 1
  • Caroline Ho
    • 1
  • May Omori
    • 1
  • Chris Proffitt
    • 1
  • Nicole Streiner
    • 1
  • William G. Rice
    • 1
  • David M. Ryckman
    • 1
  • Kenna Anderes
    • 1
  1. 1.Cylene PharmaceuticalsSan DiegoUSA