JERUSALEM - Novel tyrosine kinase blockers, “tyrphostins,“ are being enlisted in the fight against cancer, autoimmune disease and other disorders.
“During the past two years we have shown that these novel tyrosine kinase blockers are selective, nontoxic and reversible inhibitors of smooth muscle cell proliferation, with very mild and non-significant inhibition of endothelial cells' proliferation,“ said Alexander Levitzki, professor of biological chemistry at Hebrew University of Jerusalem.
Tyrphostins, which stands for tyrosine phosphorylation inhibitors, were first synthesized and described in 1988 by Levitzki and his colleagues, principally chief chemist collaborator Aviv Gazit, also of the Hebrew University. Since then Levitzki and his various associates have applied the compounds to cancer, leukemia, human papilloma virus, psoriasis and inflammatory conditions such as sepsis.
“We showed over the years that we can generate selective blockers for a large variety of tyrosine kinases, each of which is relevant to a different disease or life-threatening condition,“ Levitzki said
Current efforts are directed toward improving the potency and specificity of these agents and refining the routes of sustained delivery, added Gazit.
Sepsis Among Disorders Targeted
Early applications of tyrphostins indicated that they may be effective against inflammation. Collaborative work with a molecule, called AG556, in a dog model for sepsis was carried out with Charles Nathanson from the U.S. National Institutes of Health, in Bethesda, Md.
“This is the first agent that has been effective in vivo for sepsis. This is an enormous breakthrough because no other agent has shown such efficacy in such a faithful animal model,“ Levitzki told BioWorld International.
In psoriasis, Sugen Inc., of Redwood City, Calif., adopted a project initiated and developed by the Jerusalem team with a tyrosine kinase inhibitor. This molecule is in clinical trials at the Mount Sinai Hospital of the City University of New York.
The Sugen compound, SU5271, “is a very potent epidermal growth factor (EGF) receptor inhibitor and, formulated in an ointment, it is an excellent compound for examining the role of this receptor system in psoriatic disease,“ said Laura Shawver, vice president of preclinical and pharmaceutical development at Sugen.
For human papilloma virus 16 (HPV 16), which is a cause of cervical cancer, Levitzki and his colleagues have demonstrated in vitro that an EGF receptor blocker (AG 1478 and its analogs) and a cell cycle blocker (AG 555) are effective in blocking the growth of skin cells infected with HPV 16.
Levitzki also is evaluating use of the EGF receptor blockers in combination with the chemotherapeutic cisplatin for treatment of brain tumors. Mutated versions of the EGF receptor appear in 40 percent of brain tumor cells, conferring drug resistance. Inhibition of the receptor by AG1478 has been shown to disassociate the cells from the drug resistance. *