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.
MeSH terms
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Administration, Oral
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Animals
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Antineoplastic Agents / administration & dosage
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology
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Antineoplastic Agents / therapeutic use
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Casein Kinase II / antagonists & inhibitors*
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Casein Kinase II / metabolism
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Caspase 3 / metabolism
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Caspase 7 / metabolism
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Cell Cycle / drug effects
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Cell Line, Tumor
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Humans
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Immunohistochemistry
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Male
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Mice
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Naphthyridines / chemistry
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Naphthyridines / pharmacology
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Naphthyridines / therapeutic use*
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Phenazines
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Phosphorylation / drug effects
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Prostatic Neoplasms / drug therapy*
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Prostatic Neoplasms / enzymology
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Prostatic Neoplasms / pathology
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Protein Kinase Inhibitors / administration & dosage
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Protein Kinase Inhibitors / chemistry
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Protein Kinase Inhibitors / pharmacology
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Protein Kinase Inhibitors / therapeutic use*
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Small Molecule Libraries / administration & dosage
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Small Molecule Libraries / chemistry
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Small Molecule Libraries / pharmacology
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Small Molecule Libraries / therapeutic use*
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Structure-Activity Relationship
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Xenograft Model Antitumor Assays*
Substances
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Antineoplastic Agents
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Naphthyridines
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Phenazines
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Protein Kinase Inhibitors
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Small Molecule Libraries
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silmitasertib
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Casein Kinase II
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Caspase 3
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Caspase 7