Limited selectivity of a synthetic erbstatin derivative for tyrosine kinase and cell growth inhibition.

The natural tyrosine kinase inhibitor erbstatin and a synthetic analog (1302) were co0pared for their inhibitory activity on EGF receptor kinase, PDGF receptor kinase and a src-type kinase from bovine brain. Erbstatin inhibited both growth factor receptor kinases equally well and had little effect on the src kinase. The analog exhibited similar potency for inhibition of purified EGF receptor tyrosine kinase as erbstatin, however, was clearly less effective for inhibition of purified PDGF receptor kinase as well as the src-type kinase. The selectivity was, however, not seen when the derivative was assayed with respect to inhibition of autophosphorylation of both growth factor receptors in Swiss 3T3 cell membranes. The latter finding might explain a lack of selectivity of the compound for inhibition of DNA synthesis in 3T3 cells when the cells were stimulated comparatively with EGF, insulin, EGF plus insulin or PDGF. The results suggest that the environment of growth factor receptors in the cell membrane can remarkably modify their susceptibility to tyrosine kinase inhibitors.