By David N. Leff

Putting your car key into the ignition is a little like contacting a protein with its receptor.

Turning that key activates the starter, and sends a spark into the cylinder. In the same way, a hormone or growth factor activates its receptor to order changes in its cell.

And just as only your car key can turn on the ignition of your specific automobile, only that protein's specific receptor responds to that activation.

Pushing the analogy just a little further, the cellular skeleton key of that process is an all-purpose molecule called protein tyrosine kinase (PTK).

So, when an insulin hormone, for example, contacts its receptor, that stimulus starts a metabolic process that eventually leads to glucose transport. The point is, that insulin receptor is a tyrosine kinase.

Molecular biologist Joseph Schlessinger, who chairs pharmacology at New York University (NYU), explained: "PTK is an enzyme that takes the third phosphate of adenosine triphosphate (ATP), and incorporates it on residues of different proteins. That generates the intracellular signal that insulin — in this case — is responsible for."

Schlessinger continued: "There are at least 100 enzymes of the same PTK family, most of them receptors that regulate many important processes. If you have too strong a signal — if the receptor is hyperactive, too abundant -- you usually get too much cell growth, cancer. Too weak a signal can cause embryonic developmental problems, such as dwarfism."

Two PTK Inhibitors Targeted For Many Diseases

Specific disorders laid at the door of PTK receptors gone wrong include breast, ovarian, pancreatic and prostate cancer, Kaposi's sarcoma, heart disease, rheumatoid arthritis, atherosclerosis and bone deformities.

To control and correct these aberrant clinical conditions, drug discoverers are looking for compounds that can inhibit PTK receptors targeted at specific diseases. Among these is Sugen Inc., of Redwood City, Calif., a company co-founded by Schlessinger in 1991.

He is senior author of a paper in today's Science, titled: "Structures of the tyrosine kinase domain of fibroblast growth factor receptor in complex with inhibitors."

"The three-dimensional X-ray crystallography done in my lab at NYU," Schlessinger told BioWorld Today, "gave us the structures of two PTK inhibitors. One is rather promiscuous; it blocks many kinases. The other is very specific for the fibroblast growth factor (FGF) receptor, which is active in cancer.

"When we compared these two structures," he pointed out, "the specific and the non-specific, we were able to learn how specificity can be determined. The non-specific inhibitor blocks all the PTK receptors in vitro and in vivo. The specific inhibitor blocks only the one of interest."

Gerald McMahon, a co-author of the Science paper, directs drug discovery at Sugen. He told BioWorld Today: "We had performed a random screening here at Sugen with synthetic molecules, using tyrosine kinases. What we found was that the chemical class represented by these two molecules in the crystal are effective at inhibiting various types of PTKs.

"When Schlessinger said that he had worked out a procedure to crystalize the fibroblast growth factor receptor," McMahon added, "we dipped into Sugen's repository of molecules, and with him, attempted to co-crystallize maybe 20 or 30 that might be interesting to resolve structurally."

Schlessinger continued: "So the next step now being taken by Sugen, is to use combinatorial chemistry plus this structural information, because we know now what cavity we have to fill in the molecule, in order to mediate specificity. The company is now generating hundreds of new compounds, which will be specific for different diseases."

Sugen had previously discovered other PTK-blocking compounds, one of which is now completing Phase II trials, treating glioblastomas at Memorial Sloan Kettering Cancer Center in New York. Four more such studies are ongoing at centers in Arizona, California, Texas and the District of Columbia. "It's important to understand how these inhibitors work," Schlessinger observed, "and generate new ones, which will have less adverse effects."

IND Next Month; Clinical Trials This Summer

Co-author K. Peter Hirth is Sugen's executive vice president and chairman of research and development. He told BioWorld Today, "From a development point of view, solving the crystal structure, and telling us how these compounds work, has now enabled Sugen to synthesize a huge collection of compounds that have the capabiliies of blocking kinases.

"It has also enabled us now to make modifications on the compounds," Hirth went on, "so we can increase their solubility and bioiavailablity. We could have done so otherwise, but it would have taken us a very long time to get there. Actually, we have already done some of them, and they concern exactly what we have seen in the crystal structure."

Sugen, Hirth said, "is planning to file an IND [investigational new drug] application next month for one of these compounds. It will go into the clinic this summer, initially for inhibition of tumor angiogenesis. "We can attack the vasculature of the endothelial cells that make up the new blood vessels, which provide nutrients to the tumor," he observed. (See BioWorld Today, Aug. 5, 1996, p. 1). *