SPECIFIC-INHIBITION OF INSULIN-LIKE GROWTH-FACTOR-I AND INSULIN-RECEPTOR TYROSINE KINASE-ACTIVITY AND BIOLOGICAL FUNCTION BY TYRPHOSTINS

A series of the synthetic protein tyrosine kinase inhibitors known as tyrphostins were studied for their effect on insulin-like growth facto r-1 and insulin-stimulated cellular proliferation on NIH-3T3 fibroblas ts overexpressing either receptor, as well as for their ability to inh ibit ligand-stimulated receptor autophosphorylation and tyrosine kinas e activity toward exogenous substrates. Several of the tyrphostins tes ted demonstrated a dramatic effect by inhibiting hormone-stimulated ce ll proliferation, with IC(50)s in the submicromolar range, while being unable to block serum-stimulated cell proliferation. The tyrphostins also inhibited receptor autophosphorylation and tyrosine kinase activi ty, with a higher IC50, in the micromolar range. Most of the tyrphosti ns tested presented no clear preference for either receptor, although two of them (AG1024 and AG1034) showed significantly lower IC(50)s for IGF-1 than for insulin receptors. These results suggest that, in spit e of the high homology of the kinase regions of both receptors, it cou ld be possible to design and synthesize small molecules capable of dis criminating between them. The syn thesis of such specific inhibitors c ould be an excellent tool to establish the precise signalling mechanis ms that distinguish between the different effects of these two hormone s.