Pre-clinical characterization of CX-4945, a potent and selective small molecule inhibitor of CK2 for the treatment of cancer
| Autor: | Chris Proffitt, Johnny Y. Nagasawa, Levan Darjania, Eric Stefan, Ryan Stansfield, Sean O'Brien, Nicole Streiner, Jeffrey P. Whitten, Joshua R. Bliesath, Peter C. Chua, Caroline B. Ho, Pauline Bourbon, William G. Rice, Fabrice Pierre, Adam Siddiqui-Jain, Ta Kung Chen, Kenna Anderes, Anne Vialettes, Mustapha Haddach, David M. Ryckman, Michael K. Schwaebe, Denis Drygin, Jerome Michaux, May Omori |
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| Rok vydání: | 2011 |
| Předmět: |
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Clinical Biochemistry Administration Oral Antineoplastic Agents Pharmacology Biology Small Molecule Libraries Mice Structure-Activity Relationship Prostate cancer In vivo Cell Line Tumor medicine Animals Humans Naphthyridines Phosphorylation Casein Kinase II Protein Kinase Inhibitors Molecular Biology Protein kinase B PI3K/AKT/mTOR pathway Caspase 7 Caspase 3 Cell Cycle Prostatic Neoplasms Cancer Cell Biology General Medicine medicine.disease Immunohistochemistry Xenograft Model Antitumor Assays Apoptosis Cancer cell Phenazines |
| Zdroj: | Molecular and Cellular Biochemistry. 356:37-43 |
| ISSN: | 1573-4919 0300-8177 |
| DOI: | 10.1007/s11010-011-0956-5 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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