Selective inhibition of tyrosine protein kinase by a synthetic multisubstrate analog

Synthetic compounds were designed in an attempt to mimic the possible transition state of tyrosine protein kinases. One representative compound (RP 53801) inhibited the enzyme purified from RSV-transformed cells. A serine/threonine kinase (kinase C) was 45 fold less sensitive. The inhibition was competitive with respect to ATP and noncompetitive with respect to the phosphate acceptor poly glu4-tyr1. The degree of inhibition (IC50 = 22 microM) was however lower than that expected from a transition state analog. The compound was capable of reducing tyrosine protein kinase activity in intact cells with some selectivity at 100 microM.