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Ethyl 2-(benzylidene)-7-methyl-3-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyrimidine-6-carboxylate analogues as a new scaffold for protein kinase casein kinase 2 inhibitor

 Cheng-Hao Jin  ;  Kyu-Yeon Jun  ;  Eunjung Lee  ;  Seongrak Kim  ;  Youngjoo Kwon  ;  Kunhong Kim  ;  Younghwa Na 
 BIOORGANIC & MEDICINAL CHEMISTRY, Vol.22(17) : 4553-4565, 2014 
Journal Title
Issue Date
Antineoplastic Agents/chemical synthesis ; Antineoplastic Agents/chemistry ; Antineoplastic Agents/pharmacology* ; Apoptosis/drug effects ; Casein Kinase II/antagonists & inhibitors* ; Casein Kinase II/metabolism ; Catechols/chemical synthesis ; Catechols/chemistry ; Catechols/pharmacology* ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Dose-Response Relationship, Drug ; Drug Screening Assays, Antitumor ; Hep G2 Cells ; Heterocyclic Compounds, 2-Ring/chemical synthesis ; Heterocyclic Compounds, 2-Ring/chemistry ; Heterocyclic Compounds, 2-Ring/pharmacology* ; Humans ; Molecular Docking Simulation ; Molecular Structure ; Protein Kinase Inhibitors/chemical synthesis ; Protein Kinase Inhibitors/chemistry ; Protein Kinase Inhibitors/pharmacology* ; Structure-Activity Relationship ; Tumor Cells, Cultured
ATP binding site ; Protein kinase casein kinase 2 (PKCK2) ; Selective PKCK2 inhibitor
Protein kinase casein kinase 2 (PKCK2) is a constitutively active, growth factor-independent serine/threonine kinase, and changes in PKCK2 expression or its activity are reported in many cancer cells. To develop a novel PKCK2 inhibitor(s), we first performed cell-based phenotypic screening using 4000 chemicals purchased from ChemDiv chemical libraries (2000: randomly selected; 2000: kinase-biased) and performed in vitro kinase assay-based screening using hits found from the first screening. We identified compound 24 (C24)[(Z)-ethyl 5-(4-chlorophenyl)-2-(3,4-dihydroxybenzylidene)-7-methyl-3-oxo-3,5-dihydro-2H-thiazolo[3,2-a] pyrimidine-6-carboxylate] as a novel inhibitor of PKCK2 that is more potent and selective than 4,5,6,7-tetrabromobenzotriazole (TBB). In particular, compound 24 [half maximal inhibitory concentration (IC50)=0.56μM] inhibited PKCK2 2.2-fold more efficiently than did TBB (IC50=1.24μM), which is quite specific toward PKCK2 with respect to ATP binding, in a panel of 31 human protein kinases. The Ki values of compound 24 and TBB for PKCK2 were 0.78μM and 2.70μM, respectively. Treatment of cells with compound 24 inhibited endogenous PKCK2 activity and showed anti-proliferative and pro-apoptotic effects against stomach and hepatocellular cancer cell lines more efficiently than did TBB. As expected, compound 24 also enabled tumor necrosis factor-related apoptosis inducing ligand (TRAIL)-resistant cancer cells to be sensitive toward TRAIL. In comparing the molecular docking of compound 24 bound to PKCK2α versus previously reported complexes of PKCK2 with other inhibitors, our findings suggest a new scaffold for specific PKCK2α inhibitors. Thus, compound 24 appears to be a selective, cell-permeable, potent, and novel PKCK2 inhibitor worthy of further characterization.
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1. College of Medicine (의과대학) > Dept. of Biochemistry and Molecular Biology (생화학-분자생물학교실) > 1. Journal Papers
Yonsei Authors
Kim, Kun Hong(김건홍) ORCID logo https://orcid.org/0000-0001-5639-6372
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