Inhibition of calcineurin by the tyrphostin class of tyrosine kinase inhibitors.
Because of their similarity to tyrosine, members of the tyrphostin family of tyrosine kinase inhibitors were tested as possible inhibitors of the protein serine/threonine phosphatase calcineurin. Calcineurin was inhibited by tyrphostins A8 (also designated AG10), A23 (AG18), and A48 (AG112) with p-nitrophenyl phosphate as substrate. The IC50 values estimated with this substrate were 21, 62, and 30 microM for A8, A23, and A48, respectively. Two other tyrphostins, A46 (AG99) and A63 (AG13), did not inhibit calcineurin at concentrations up to 200 microM. Similar inhibition was observed with tyrphostins A8 and A23 using a phosphopeptide substrate (1.0 mM). Tyrphostin A8 showed competitive inhibition against p-nitrophenyl phosphate as the substrate, with an inhibition constant of 18 microM, comparable to the IC50 value. Possible chemical and structural features influencing inhibition are discussed based on a comparison of the structures of the tyrphostins tested.
Martin
B L
BL
Department of Biochemistry, University of Tennessee, Memphis 38163, USA. bmartin@utmem1.utmem.edu
D065095:Calcineurin Inhibitors; D002396:Catechols / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D009570:Nitriles / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D020032:Tyrphostins
D065095:Calcineurin Inhibitors; D002396:Catechols; D004791:Enzyme Inhibitors; D009570:Nitriles; D020032:Tyrphostins; C086599:tyrphostin A46; D011505:Protein-Tyrosine Kinases; C060641:tyrphostin A23