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Specific Inhibition of Insulin-Like Growth Factor-1 and Insulin Receptor Tyrosine Kinase Activity and Biological Function by Tyrphostins

Diabetes Branch (M.P., D.L.), National Institute of Diabetes, Digestive and Kidney Diseases, NIH, Bethesda, Maryland 20892; Department of Biological Chemistry (A.G., A.L.), Alexander Silberman Institute of Life Sciences, Hebrew University of Jerusalem, Jerusalem 91904, Israel; and Department of Pathology (E.W.), Sackler School of Medicine, Tel Aviv University, Ramat Aviv, Tel Aviv 69978 Israel

Address all correspondence and requests for reprints to: Derek LeRoith, Diabetes Branch, NIDDK, NIH, Building 10, Room 8S235A, 10 Center Drive, MSC-1770, Bethesda, Maryland 20892-1770. E-mail: Derek{at}helix.nih.gov

A series of the synthetic protein tyrosine kinase inhibitors known as tyrphostins were studied for their effect on insulin-like growth factor-1 and insulin-stimulated cellular proliferation on NIH-3T3 fibroblasts overexpressing either receptor, as well as for their ability to inhibit ligand-stimulated receptor autophosphorylation and tyrosine kinase activity toward exogenous substrates. Several of the tyrphostins tested demonstrated a dramatic effect by inhibiting hormone-stimulated cell proliferation, with IC₅₀s in the submicromolar range, while being unable to block serum-stimulated cell proliferation. The tyrphostins also inhibited receptor autophosphorylation and tyrosine kinase activity, with a higher IC₅₀, in the micromolar range. Most of the tyrphostins tested presented no clear preference for either receptor, although two of them (AG1024 and AG1034) showed significantly lower IC₅₀s for IGF-1 than for insulin receptors. These results suggest that, in spite of the high homology of the kinase regions of both receptors, it could be possible to design and synthesize small molecules capable of discriminating between them. The synthesis of such specific inhibitors could be an excellent tool to establish the precise signalling mechanisms that distinguish between the different effects of these two hormones.

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