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Title of Journal: Mol Cell Biochem

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Abbravation: Molecular and Cellular Biochemistry

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Springer US

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DOI

10.1007/978-0-387-34727-1_16

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ISSN

1573-4919

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Preclinical characterization of CX4945 a potent

Authors: Fabrice Pierre Peter C Chua Sean E O’Brien Adam SiddiquiJain 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
Publish Date: 2011/07/14
Volume: 356, Issue: 1-2, Pages: 37-
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Abstract

In this article we describe the preclinical characterization of 53chlorophenylamino benzoc26naphthyridine8carboxylic acid CX4945 the first orally available small molecule inhibitor of protein CK2 in clinical trials for cancer CX4945 was optimized as an ATPcompetitive inhibitor of the CK2 holoenzyme Ki = 038 nM Iterative synthesis and screening of analogs guided by molecular modeling led to the discovery of orally available CX4945 CK2 promotes signaling in the Akt pathway and CX4945 suppresses the phosphorylation of Akt as well as other key downstream mediators of the pathway such as p21 CX4945 induced apoptosis and caused cell cycle arrest in cancer cells in vitro CX4945 exhibited a dosedependent antitumor activity in a xenograft model of PC3 prostate cancer model and was well tolerated In vivo timedependent reduction in the phosphorylation of the biomarker p21 at T145 was observed by immunohistochemistry Inhibition of the newly validated CK2 target by CX4945 represents a fresh therapeutic strategy for cancer

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