A novel class of low molecular weight protein tyrosine kinase inhibitors is described. These compounds constitute a systematic series of molecules with a progressive increase in affinity toward thesubstrate site of the EGF receptor kinase domain. These competitive inhibitors also effectively block the EGF-dependent autophosphorylation of the receptor. The potent EGF receptor kinase blockers examined were found to competitively inhibit the homologous insulin receptorkinase at 102-103 higher inhibitor concentrations in spite of the significant homology between these protein tyrosine kinases. These results demonstratethe ability to synthesize selective tyrosine kinase inhibitors. The most potent EGF receptor kinase inhibitors also inhibit the EGF-dependent proliferation of A431/clone 15 cells with little or no effect on EGF independent cell growth. These results demonstrate the potential use of protein tyrosine kinase inhibitors as selective antiproliferative agents for proliferative diseases caused by the hyperactivity of protein tyrosine kinases. We have suggested the name“tyrphostins” for this class of antiproliferative compounds which act as protein tyrosinekinase blockers.

Among the numerous oncogene products, many exhibit protein tyrosine kinase (PTK) activity, which is essential for their biological activity (see ref 1 and 2, for review). Similarly, the initial event in mitogenesis induction by plasma growth factors is the ligand-induced auto-phosphorylation of the cell surface receptor and the phosphorylation of a host of intracellular substrates. 2'9 Similarly, the hormone insulin induces autophosphorylation of its receptor on specific tyrosine residues as well as hormone-induced tyrosine phosphorylation of intracellular target proteins.(See ref 10, for review.) Site-directed mutagenesis within the insulin receptor10 and the epidermal growth factor (EGF) receptor11, 12 molecules