Judicious Application of Allyl Protecting Groups for the Synthesis of 2-Morpholin-4-yl-4-oxo-4H-chromen-8-yl Triflate, a Key Precursor of DNA-Dependent Protein Kinase Inhibitors

2006 ◽  
Vol 8 (26) ◽  
pp. 5927-5929 ◽  
Author(s):  
Sonsoles Rodriguez Aristegui ◽  
Marine Desage El-Murr ◽  
Bernard T. Golding ◽  
Roger J. Griffin ◽  
Ian R. Hardcastle
Keyword(s):  
Protein Kinase ◽  
Kinase Inhibitors ◽  
Protein Kinase Inhibitors ◽  
Protecting Groups ◽  
Dependent Protein Kinase ◽  
Dependent Protein ◽  
Allyl Protecting Groups

Receptor-mediated endocytosis of urokinase-type plasminogen activator is regulated by cAMP-dependent protein kinase

1997 ◽  
Vol 110 (12) ◽  
pp. 1395-1402 ◽  
Author(s):  
L. Goretzki ◽  
B.M. Mueller
Keyword(s):  
Protein Kinase ◽  
Plasminogen Activator ◽  
Kinase Inhibitors ◽  
Melanoma Cells ◽  
Protein Kinase Inhibitors ◽  
Dependent Protein Kinase ◽  
Camp Dependent Protein Kinase ◽  
Type Plasminogen Activator ◽  
Urokinase Type Plasminogen Activator ◽  
Dependent Protein

Internalization of the urokinase-type plasminogen activator (uPA) requires two receptors, the uPA receptor (uPAR) and the low density lipoprotein receptor-related protein (LRP)/alpha2-macroglobulin (alpha2M) receptor. Here, we address whether protein kinases are involved in the internalization of uPA by human melanoma cells. Initially, we found that the internalization of uPA was significantly inhibited by the serine/threonine protein kinase inhibitors staurosporine, K-252a and H-89, but not by the tyrosine kinase inhibitors, genistein and lavendustin A. Internalization of uPA was also inhibited by a pseudosubstrate peptide for cAMP-dependent protein kinase (PKA), but not by a pseudosubstrate peptide for protein kinase C. We confirmed a requirement for PKA-activity and implicated a specific isoform by using an antisense oligonucleotide against the regulatory subunit RI alpha of PKA which suppresses PKA-I activity. Exposure of cells to this oligonucleotide led to a specific, dose-dependent decrease in RI alpha protein and to a significant inhibition in the rate of uPA internalization. We further demonstrate that treatment of melanoma cells with either H-89 or PKA RI alpha antisense oligonucleotides also resulted in a decreased internalization of two other ligands of LRP, activated alpha2M and lactoferrin, indicating that PKA activity is associated with LRP. Finally, we demonstrate that PKA activity is also required for the internalization of transferrin, but not for the internalization of the epidermal growth factor or adenovirus 2, suggesting that in melanoma cells, PKA activity is not generally required for clathrin-mediated endocytosis, but is rather associated with specific internalization receptors.

Protein kinase inhibitors reduce SR Ca transport in permeabilized cardiac myocytes

1994 ◽  
Vol 267 (2) ◽  
pp. H812-H820 ◽  
Author(s):  
A. Mattiazzi ◽  
L. Hove-Madsen ◽  
D. M. Bers
Keyword(s):  
Protein Kinase ◽  
Kinase Inhibitors ◽  
Inhibitory Effect ◽  
Ruthenium Red ◽  
Protein Kinase Inhibitors ◽  
Inhibitory Peptide ◽  
Dependent Protein Kinase ◽  
Ca Transport ◽  
Ca Uptake ◽  
Dependent Protein

Phosphorylation of the sarcoplasmic reticulum (SR) protein phospholamban by adenosine 3',5'-cyclic monophosphate (cAMP)-dependent protein kinase (PKA) and Ca-calmodulin-dependent protein kinase (CaM-KII) stimulates Ca-adenosinetriphosphatase (ATPase) activity and SR Ca transport, but the role of CaM-KII-dependent phosphorylation is not well defined. We studied the PKA- and CaM-KII-dependent regulation of SR Ca transport in digitonin-permeabilized rabbit ventricular myocytes. SR Ca uptake and free Ca concentration were measured on line with indo 1 and Ca electrodes in the presence of 20 microM ruthenium red and 10 mM oxalate. neither N5,2'-w-dibutyryl-cAMP (up to 500 microM) nor the nonhydrolyzable cAMP agonist adenosine 3'5'-cyclic monophosphorothioate sodium salt (Sp-cAMP[S]; up to 275 microM) affected the maximum uptake rate (Vmax) or the dissociation constant (Kd) for Ca uptake. However, the PKA inhibitor H-89 significantly increased Kd (e.g., from 307 +/- 67 to 826 +/- 62 nM Ca at 40-65 microM H-89) without significantly affecting Vmax. Both CaM-KII inhibitors, KN-62 (60 microM) and a CaM-KII inhibitory peptide (10 microM), significantly decreased Vmax from 11.95 +/- 0.5 to 9.48 +/- 0.6 nmol.mg-1.min-1 and from 10.95 +/- 1.72 to 7.37 +/- 0.94 nmol.mg-1.min-1, respectively, without consistently changing Kd. The effects of H-89 on Kd and of KN-62 on Vmax were prevented by a monoclonal antibody to phospholamban 2D12 (consistent with the antibody removing the inhibitory effect of phospholamban on the SR Ca-ATPase).(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals Selective inhibition of intestinal guanosine 3′,5′-cyclic monophosphate signaling by small-molecule protein kinase inhibitors

2018 ◽  
Vol 293 (21) ◽  
pp. 8173-8181 ◽  
Author(s):  
Marcel J. C. Bijvelds ◽  
Gary Tresadern ◽  
Ann Hellemans ◽  
Karine Smans ◽  
Natascha D. A. Nieuwenhuijze ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Small Molecule ◽  
Kinase Inhibitors ◽  
Selective Inhibition ◽  
Protein Kinase Inhibitors ◽  
Secretory Diarrhea ◽  
Dependent Protein Kinase ◽  
Anion Secretion ◽  
Cyclic Monophosphate ◽  
Dependent Protein

The guanosine 3′,5′-cyclic monophosphate (cGMP)-dependent protein kinase II (cGKII) serine/threonine kinase relays signaling through guanylyl cyclase C (GCC) to control intestinal fluid homeostasis. Here, we report the discovery of small-molecule inhibitors of cGKII. These inhibitors were imidazole-aminopyrimidines, which blocked recombinant human cGKII at submicromolar concentrations but exhibited comparatively little activity toward the phylogenetically related protein kinases cGKI and cAMP-dependent protein kinase (PKA). Whereas aminopyrimidyl motifs are common in protein kinase inhibitors, molecular modeling of these imidazole-aminopyrimidines in the ATP-binding pocket of cGKII indicated an unconventional binding mode that directs their amine substituent into a narrow pocket delineated by hydrophobic residues of the hinge and the αC-helix. Crucially, this set of residues included the Leu-530 gatekeeper, which is not conserved in cGKI and PKA. In intestinal organoids, these compounds blocked cGKII-dependent phosphorylation of the vasodilator-stimulated phosphoprotein (VASP). In mouse small intestinal tissue, cGKII inhibition significantly attenuated the anion secretory response provoked by the GCC-activating bacterial heat-stable toxin (STa), a frequent cause of infectious secretory diarrhea. In contrast, both PKA-dependent VASP phosphorylation and intestinal anion secretion were unaffected by treatment with these compounds, whereas experiments with T84 cells indicated that they weakly inhibit the activity of cAMP-hydrolyzing phosphodiesterases. As these protein kinase inhibitors are the first to display selective inhibition of cGKII, they may expedite research on cGMP signaling and may aid future development of therapeutics for managing diarrheal disease and other pathogenic syndromes that involve cGKII.

Disruption of epithelial tight junctions is prevented by cyclic nucleotide-dependent protein kinase inhibitors

2000 ◽  
Vol 113 (5) ◽  
pp. 349-361 ◽  
Author(s):  
Cécile Klingler ◽  
Uwe Kniesel ◽  
Simon D. Bamforth ◽  
Hartwig Wolburg ◽  
Britta Engelhardt ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Tight Junctions ◽  
Cyclic Nucleotide ◽  
Kinase Inhibitors ◽  
Protein Kinase Inhibitors ◽  
Dependent Protein Kinase ◽  
Dependent Protein ◽  
Epithelial Tight Junctions

scholarly journals cGMP-Dependent Protein Kinase Inhibitors in Health and Disease

2013 ◽  
Vol 6 (2) ◽  
pp. 269-286 ◽  
Author(s):  
Stefanie Wolfertstetter ◽  
Johannes Huettner ◽  
Jens Schlossmann
Keyword(s):  
Protein Kinase ◽  
Kinase Inhibitors ◽  
Protein Kinase Inhibitors ◽  
Dependent Protein Kinase ◽  
Cgmp Dependent Protein Kinase ◽  
Dependent Protein ◽  
Health And Disease
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