Protein tyrosine kinase inhibitors as novel therapeutic agents

Protein tyrosine kinases (PTKs) play a key role in normal cell and tissue d evelopment. Enhanced PTK activity is intimately correlated with proliferati ve diseases, such as cancers, leukemias, psoriasis, and restenosis. This re alization prompted us to systematically synthesize tyrosine phosphorylation inhibitors (tyrphostins) as potential drugs. Over the years, we have demon strated the ability to synthesize selective tyrphostins aimed at different receptor, as well as at nonreceptor, tyrosine kinases. Some of these tyrpho stins have shown efficacy in vivo as antileukemic agents and antirestenosis agents. AG 490, a Jak-2 inhibitor, is potent against recurrent pre-B acute lymphoblastic leukemia. AG 1295, a selective platelet-derived growth facto r receptor kinase inhibitor, inhibits 50% of balloon injury-induced stenosi s in the phemoral arteries of pigs. AG 1517 (SU 5271), a potent epiderminal growth factor receptor kinase inhibitor, is currently in clinical trials f or psoriasis. Similarly, SU 5416, a potent kinase inhibitor of the vascular endothelial growth factor receptor/kinase domain receptor/Flk-1, is curren tly in clinical trials as an anticancer agent by virtue of its strong anti angiogenic activity. These findings demonstrate that the identification of PTKs that play a key role in a defined disease state can lead to a selectiv e drug. Tyrphostins also show efficacy in vivo in inflammatory diseases suc h as sepsis, cirrhosis, and experimental autoimmune encephalitis. (C) 1999 Elsevier Science Inc. All rights reserved.