Alexander Levitzki#

Short laudation by Moshe Yaniv#

A.Levitzki started as an enzymologist who demonstrated negative cooperativity in enzymes and receptors initially with Daniel E.Koshland,Jr., and then in his own laboratory. The molecular basis of this phenomenon was determined and "half-of-the-sites" reactivity, later to be found in many oligomeric proteins, was demonstrated in enzymes. He pursued his research by developing a radio-ligand binding assay for β-adrenoceptors that allowed, for the first time, the identification of these important and ubiquitous receptors.

He has later undertaken a comprehensive analysis of the mode of adenylyl cyclase activation by the receptors; many of the issues were later found relevant to many other G protein activated systems.

The Levitzki group was the first to develop methodologies to reconstitute the β-receptor—G protein—cyclase, still the only receptor system to be reconstituted from its purified and separate components. This system reaffirmed the validity of the mode of coupling between the receptor and the Gs protein activated cyclase.

Since the mid-1980s, the Levitzki laboratory has been developing the approach of "signal transduction therapy". The laboratory has developed protein tyrosine kinase inhibitors, also known as "tyrphostins" (tyrosine phosphorylation inhibitors), as lead compounds to combat proliferative diseases. The group was also the first to demonstrate that PTK inhibitors that block Her-2/neu sensitize lung cancer cells to killing by the pro-apoptotic cytotoxic agents CDDP, doxorubicin and etoposide .The group, in collaboration with Sugen (now Pfizer), was the first to show the efficacy of VEGFR/KDR inhibitors as anti—angiogenic agents and was the first to demonstrate the anti-tumour effects in vivo. The group pioneered the development of tyrosine kinase inhibitors for the treatment of CML which formed the basis for the development of Gleevec in the late l990s.

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