ABSTRACT
Protein kinase CK2 ("casein kinase II") is a protein serine/threonine kinase that plays critical roles in biological processes such as cell growth, cell cycle progression, and apoptosis. So far, we have identified that one catalytic isozyme of CK2, CK2α, is over-expressed in the kidney during the progression of glomerulonephritis (GN). Moreover, we have shown that in vivo inhibition of CK2 by administration of CK2 inhibitors was effective in the treatment of experimental GN. Hence the development of potent CK2 inhibitors should be considered in therapeutic strategies for GN. In the present study we identified compound 13, a pyrazine derivative, as a potent CK2 inhibitor. By performing enzyme kinetics analysis in vitro, we characterized the inhibition of compound 13 toward each CK2 catalytic isozyme. Furthermore, in vivo, we demonstrated that compound 13 is effective in attenuating proteinuria, decreasing the enhanced level of blood urea nitrogen and serum creatinine, and ameliorating glomerular crescent formation in an experimental GN rat model. On the other hand, cellular apoptosis was detected in the rat testis following administration of compound 13. This study provides clues for new strategies for developing applicable compounds into CK2-targeted GN treatments.
Subject(s)
Casein Kinase II/antagonists & inhibitors , Glomerulonephritis/drug therapy , Protein Kinase Inhibitors/therapeutic use , Animals , Apoptosis , Blood Urea Nitrogen , Casein Kinase II/metabolism , Creatinine/blood , Emodin/pharmacology , Emodin/therapeutic use , Glomerulonephritis/metabolism , Kidney Glomerulus/drug effects , Kidney Glomerulus/metabolism , Kidney Glomerulus/pathology , Male , Protein Kinase Inhibitors/pharmacology , Proteinuria , Pyrazines/pharmacology , Pyrazines/therapeutic use , Rats, Inbred WKY , Testis/drug effects , Testis/pathologyABSTRACT
Pyrazolo[4,3-b]indole derivatives have been designed as novel CK2 inhibitor compounds based on the binding mode analysis of a previously reported phenylpyrazole-type CK2 inhibitor. A series of pyrazolo[4,3-b]indoles and related dihydropyrazolo[4,3-b]indoles were efficiently prepared from simple starting materials using a gold-catalysed three-component annulation reaction as a key step. Several of the newly synthesized compounds displayed high levels of inhibitory activity, indicating that the pyrazolo[4,3-b]indole core represents a promising scaffold for the development of potent CK2 inhibitors.
Subject(s)
Casein Kinase II/antagonists & inhibitors , Gold/chemistry , Indoles/pharmacology , Protein Kinase Inhibitors/pharmacology , Pyrazoles/pharmacology , Casein Kinase II/metabolism , Catalysis , Dose-Response Relationship, Drug , Humans , Indoles/chemical synthesis , Indoles/chemistry , Molecular Structure , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Pyrazoles/chemical synthesis , Pyrazoles/chemistry , Structure-Activity RelationshipABSTRACT
Two classes of fused nitrogen heterocycles were designed as CK2 inhibitor candidates on the basis of previous structure-activity relationship (SAR) studies. Various dipyrrolo[3,2-b:2',3'-e]pyridine and benzo[g]indazole derivatives were prepared using transition-metal-catalysed cascade and/or multicomponent reactions. Biological evaluation of these candidates revealed that benzo[g]indazole is a promising scaffold for potent CK2 inhibitors. The inhibitory activities on cell proliferation of these potent CK2 inhibitors are also presented.
Subject(s)
Casein Kinase II/antagonists & inhibitors , Copper/chemistry , Gold/chemistry , Heterocyclic Compounds/chemistry , Nitrogen Compounds/chemistry , Protein Kinase Inhibitors/chemical synthesis , Catalysis , Cell Line, Tumor , Cell Proliferation/drug effects , Heterocyclic Compounds/pharmacology , Humans , Models, Molecular , Molecular Structure , Nitrogen Compounds/pharmacology , Protein Kinase Inhibitors/pharmacology , Structure-Activity RelationshipABSTRACT
Protein kinase CK2 (CK2) is a ubiquitous serine/threonine protein kinase for hundreds of endogenous substrates. CK2 has been considered to be involved in many diseases, including cancers. Herein we report the discovery of a novel ATP-competitive CK2 inhibitor. Virtual screening of a compound library led to the identification of a hit 2-phenyl-1,3,4-thiadiazole compound. Subsequent structural optimization resulted in the identification of a promising 4-(thiazol-5-yl)benzoic acid derivative.
