THE DEGREE OF INHIBITION OF PROTEIN-TYROSINE KINASE-ACTIVITY BY TYRPHOSTIN-23 AND 25 IS RELATED TO THEIR INSTABILITY

Tyrphostins, a series of compounds with hydroxy cis-cinnamonitrile bac kbone structures, are used as protein tyrosine kinase inhibitors to st udy signal transduction. While studying the inhibition of pp60(c-src) protein tyrosine kinase activity with tyrphostins 23 and 25 (3,4-di- a nd 3,4,5-trihydroxy cis-cinnamonitrile), we found the inhibitors to be quite unstable. The inhibition of pp60(c-src) activity corresponded t o the formation of products derived from the parent tyrphostin compoun d. One of these isolated products was at least 10-fold more inhibitory to both pp60(c-src) and epidermal growth factor receptor kinase activ ity than the parent tyrphostin. The generation of compounds more inhib itory than the parent tyrphostin may explain the delayed inhibition re ported with epidermal growth factor receptor kinase activity. Since th ese tyrphostins are unstable and form compounds more inhibitory toward s protein tyrosine kinase activity, any results obtained with these co mpounds must be interpreted with caution.