Protein tyrosine kinases (PTKs) play a key role in normal cell and tissue development. Enhanced PTK activity is intimately correlated with proliferative diseases, such as
cancers,
leukemias,
psoriasis, and restenosis. This realization prompted us to systematically synthesize
tyrosine phosphorylation inhibitors (
tyrphostins) as potential drugs. Over the years, we have demonstrated the ability to synthesize selective
tyrphostins aimed at different receptor, as well as at nonreceptor,
tyrosine kinases. Some of these
tyrphostins 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 factor receptor kinase inhibitor, inhibits 50% of balloon injury-induced
stenosis in the phemoral arteries of pigs.
AG 1517 (SU 5271), a potent epiderminal
growth factor receptor kinase inhibitor, is currently in clinical trials for
psoriasis. Similarly,
SU 5416, a potent
kinase inhibitor of the
vascular endothelial growth factor receptor/
kinase domain receptor/Flk-1, is currently 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 selective
drug.
Tyrphostins also show efficacy in vivo in inflammatory diseases such as
sepsis,
cirrhosis, and experimental
autoimmune encephalitis.