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Pre-clinical characterization of CX-4945, a potent and selective small molecule inhibitor of CK2 for the treatment of cancer.
- Source :
-
Molecular and cellular biochemistry [Mol Cell Biochem] 2011 Oct; Vol. 356 (1-2), pp. 37-43. Date of Electronic Publication: 2011 Jul 14. - Publication Year :
- 2011
-
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.
- Subjects :
- Administration, Oral
Animals
Antineoplastic Agents administration & dosage
Antineoplastic Agents chemistry
Antineoplastic Agents pharmacology
Antineoplastic Agents therapeutic use
Casein Kinase II metabolism
Caspase 3 metabolism
Caspase 7 metabolism
Cell Cycle drug effects
Cell Line, Tumor
Humans
Immunohistochemistry
Male
Mice
Naphthyridines chemistry
Naphthyridines pharmacology
Phenazines
Phosphorylation drug effects
Prostatic Neoplasms enzymology
Prostatic Neoplasms pathology
Protein Kinase Inhibitors administration & dosage
Protein Kinase Inhibitors chemistry
Protein Kinase Inhibitors pharmacology
Small Molecule Libraries administration & dosage
Small Molecule Libraries chemistry
Small Molecule Libraries pharmacology
Structure-Activity Relationship
Casein Kinase II antagonists & inhibitors
Naphthyridines therapeutic use
Prostatic Neoplasms drug therapy
Protein Kinase Inhibitors therapeutic use
Small Molecule Libraries therapeutic use
Xenograft Model Antitumor Assays
Subjects
Details
- Language :
- English
- ISSN :
- 1573-4919
- Volume :
- 356
- Issue :
- 1-2
- Database :
- MEDLINE
- Journal :
- Molecular and cellular biochemistry
- Publication Type :
- Academic Journal
- Accession number :
- 21755459
- Full Text :
- https://doi.org/10.1007/s11010-011-0956-5