Thiazolidine-diones. Biochemical and biological activity of a novel class of tyrosine protein kinase inhibitors.
Various derivatives of thiazolidine-diones have been identified as tyrosine protein kinase inhibitors. The epidermal growth factor (EGF) receptor kinase and c-src kinase were inhibited in vitro with IC50 values in the range of 1-7 microM. The v-abl tyrosine protein kinase was not inhibited by thiazolidine-diones. Inhibition was found to be specific for tyrosine protein kinases. Inhibition of serine/threonine protein kinases was not observed. The active derivatives were shown to inhibit EGF-induced receptor autophosphorylation, either in vitro or in intact cells, and were also found to inhibit growth of the EGF-dependent BALB/MK and A431 cell lines (IC50 1-3 microM). Growth of the interleukin-3-dependent myeloid cell line FDC-P1 was inhibited with equal efficiency. Thus, in these cell lines, members of the c-src kinase family are also potential targets for inhibition by the compounds.
Geissler
J F
JF
Oncology and Virology Research Department, Ciba-Geigy Ltd., Basel, Switzerland.
Traxler
P
P
Regenass
U
U
Murray
B J
BJ
Roesel
J L
JL
Meyer
T
T
McGlynn
E
E
Storni
A
A
Lydon
N B
NB
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D066246:ErbB Receptors / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007202:Indicators and Reagents; D007700:Kinetics; D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D013844:Thiazoles / Q000138:chemical synthesis / Q000494:pharmacology*
D007202:Indicators and Reagents; D047428:Protein Kinase Inhibitors; D013844:Thiazoles; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases