By David N. Leff
MIAMI - Nearly 900 microbiologists heard molecular biophysicist Joseph Schlessinger declare here yesterday, "Now that the concept of protein tyrosine kinase [PTK] inhibitors has been validated, we will see a lot of new drugs in the pipeline in the next millennium. And I think we will have the first drugs from this harvest probably in 2001 - but, you know, the devil is in the details."
Schlessinger was addressing yesterday's session of the 1999 Miami/Nature Biotechnology Winter Symposium. Its theme this year is "Advances in Gene Technology: Signal Transduction and Therapeutic Strategies." He spoke upon receiving the symposium's annual Distinguished Service Award. His subject: "Cellular Signaling by Tyrosine Phosphorylation [TP]."
The awardee chairs the department of pharmacology at New York University and directs the school's Skirball Institute for Biomolecular Medicine. Schlessinger illustrated the therapeutic applications of his enzyme blocker by its treatment of tumor angiogenesis. The subject came to public prominence last year, when the New York Times reported the findings of Harvard surgeon Judah Folkman, a founding father of the field. (See BioWorld Today, May 5, 1998, p. 1.)
"I think Folkman's concept is correct," Schlessinger told his audience, "but his inhibitors are like aspirin, before we knew how aspirin works. Our particular PTK inhibitor is after we knew how aspirin works. Empirically, Folkman has something that works in vivo, but the chemistry does not tell us anything about how his inhibitors work. Here, we knew the key molecules and could design something; that's the major difference.
"What I'm presenting," Schlessinger said, "is crucial for anti-angiogenesis development. If you knock out the gene for vascular endothelial growth factor, you won't have angiogenesis and the tumor will die. So, if you generate TP inhibitors, you won't have the issue of a validation, because they're well known. You just have to improve them, but won't have to prove any more that the concept is right. So, this is what we did."
Schlessinger's PTK inhibitors are now in Phase I trials, being conducted by Sugen Inc., of South San Francisco. He is a co-founder of that company, and its chief scientist and honorary director. Trials of the inhibitor for prostate and ovarian cancers, as well as for glioblastomas, will follow, he said.
Moving Toward Commercialization
The NYU scientist drew a laugh from his audience when he described an X-ray crystallography experiment in which "our inhibitor molecule fit into the active-site groove of the enzyme as tightly as O.J. Simpson's glove."
He concluded, "Finally, this is just the tip of the drug-design iceberg, because we have been talking about all these genes that have been analyzed in the genome project, so there will be so much going on there. This will change totally the way drugs will be developed in the next century."
Schlessinger defined his current role to BioWorld Today as "trying to identify the exact, transistor-like molecular circuitry of the cell - by which I mean the atomic resolution. Once we know that, this approach can be commercialized, because a very rational way can then be applied to the development of drugs."
The symposium began Sunday, Feb. 7, with 838 registrants, said co-organizer William Whelan, director of the University of Miami's Biochemistry & Molecular Biology Foundation. Whelan said this year's roster of attendees is the most numerous in the symposium's 32-year history.
Sunday's opening session heard the traditional thematic Feodor Lynen Lectures, presented this year by James Darnell, of Rockefeller University in New York, and Tony Hunter, at the Salk Institute in La Jolla, Calif. Hunter addressed "Signaling by Protein Tyrosine Kinases and Phosphatases," and Darnell spoke on "Signaling Genes from the Cell Surface."
This year's winter symposium ends tomorrow. Next year's event, scheduled for Feb. 5-9, will deal with "DNA, RNA and Cancer."