Effect of the structure of adenosine mimic of bisubstrate-analog inhibitors on their activity towards basophilic protein kinases.
Previously reported structural fragments that associate with the ATP-binding pocket of basophilic protein kinases were conjugated with d-arginine-containing peptides. Inhibitory potency of the resulting bisubstrate-analog inhibitors towards PKA and ROCK-II extended to subnanomolar range. The conjugates incorporating 2-pyrimidyl-5-amidothiophene fragment had the highest activity and at 100 nM concentration exhibited over 80% inhibition of most of the tested basophilic kinases of the AGC group.
Institute of Chemistry, University of Tartu, 2 Jakobi St., 51014 Tartu, Estonia.
Erki
E
Enkvist
Marie
M
Kriisa
Mart
M
Roben
Grete
G
Kadak
Gerda
G
Raidaru
Asko
A
Uri
D000241:Adenosine / Q000031:analogs & derivatives* / Q000737:chemistry; D001120:Arginine / Q000737:chemistry; D001665:Binding Sites; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011743:Pyrimidines / Q000737:chemistry; D013876:Thiophenes / Q000737:chemistry; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
D010455:Peptides; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013876:Thiophenes; D001120:Arginine; D054460:rho-Associated Kinases; D017868:Cyclic AMP-Dependent Protein Kinases; D000241:Adenosine; C030986:pyrimidine