| COMMENTS |
Several factors have made it difficult to design SH2 inhibitors with selective in vivo activity, explains Tony Pawson, head of the Div of Molecular Biology & Cancer at the Samuel Lunenfeld Research Institute of Mount Sinai Hospital, Toronto. Pawson is a leading cell-signaling researcher. One problem has been "the intrinsic difficulty in finding small molecules that interfere with protein interaction which can involve quite large surface areas", Pawson says. "Further more since much of the binding energy for the formation of SH2 complexes comes from the recognition of phosphotyro sine, effective antagonists are likely to be charged compds that are inefficient at penetrating into cells. Finally, since SH2 domains only differ in their affinities for distinct sites by two orders of magnitude or so, it has been unclear how easy it would be to engineer inhibitors that are really specific in vivo" The Co.'s results "are therefore both encouraging & exciting", Pawson says, "They have designed a compd that uses Dpp to target bone & the SH2 domain phosphotyrosine binding pocket, thus making a virtue of the requirement for a phosphotyrosine mimic. The rest of the inhibitory ligand is a nonpeptide structure that aids tight & selective binding to the SH2 domain. Reassuringly, this compd shows antiosteo clast activity in an in vitro assay, & antiresorptive activity [decreased bone resorption by osteoclasts] in rats" The results are significant, Pawson adds, "because they show that modular protein-protein interactions can indeed be blocked not only in vitro, but also in a functional sense in an intact animal. This approach may therefore prove useful in the design of further compds that can be applied to the treat of bone disease". Also asked to comment on the study, David Cowburn, asso ciate prof. of physical biochemistry at Rockefeller University, New York City, says it's "quite interesting & important because it does represent the first case of designing an SH2 inhibitor with in vivo activity. And it's a pretty important pathway. There are other drugs for this pathway, but they don't have a well understood mechanism". Cowburn, who specializes in the structural biology of cell-signaling protein domains, is president designate of the New York Structural Biology Center, a collaborative research institute. When SH2 & other signal transduction domains were discovered & their three-dimensional structure determined, researchers were enthusiastic about their potential as therapeutic targets of rational drug design. "So there was a lot of interest at first", Cowburn says. "But then it wasn't easy to obtain pharmacological activity or selectivity, & the inte rest declined somewhat". The Co.'s findings may rekindle a burst of activity in this area", he says. Cowburn compares the Co.'s results to the discovery of STI- 571 a leukemia drug owned by Novartis & currently under going clinical trials. STI-571 targets a signal transduction pathway involving a mutant enzyme called Bcr-Ab1, instead of SH2 or one of the other cell-signaling protein domains. But STI-571, like present "antiosteoporosis compd.", "is a good example of using intracellular signal transduction pathways & obtaining adequate specificity, which previously had always been thought of as impractical" Cowburn says |
| SALES VALUE | The osteoporosis drug market that the Co. is targeting has annual worldwide sales of > US$ 3 billion, according to Co.'s Team leader. "It's a huge market," he says, "That's why there's a lot of competition to develop new & better drugs that are more effective, safer & orally active" |
| TECHNOLOGY |
Co.'s researchers have designed & tested compd that inhibits cell signaling by the SH2 (Src homology 2) protein in living cells & in animal tests. The compd is the first in vivo inhibitor of SH2 or any of several similar cell-signaling protein domains that have received widespread research attention in recent years. The SH2, SH3, PH (plekstrin homology), WW (tryptophan- tryptophan), & PTB (phosphotyrosine-binding) protein domains have been the focus of intensive study since they were discovered, beginning in the mid-1980s. The domains have been considered particularly promising DRUG TAR GETS because of the essential roles they play in cell signaling & in diseases such as cancer. But compds capable of inhibiting them have been elusive. Now, (See trademark) - a compd designed, synthesized, & characterized by researchers (See Author) - has been reported to inhibit the SH2 domain of Src tyrosine kinase in cellular assays & to exhibit promising activity in a rat model. Src tyrosine kinase has been implicated in the bone resorption process that takes place in osteoporosis. In an effort to develop an antiosteoporosis agent, the Co.'s researchers first obtained a crystal structure of a complex of the SH2 domain of Src tyrosine kinase bound to citrate. Based on this structure, they designed a key functional group - 3',4'-diphosphono-phenylalanine (Dpp) - to mimic a phosphotyrosine motif recognized by the SH2 domain. The researchers found that Dpp not only induced the "said compd" to bind & inhibit SH2, but also caused it to act selectively on osteoclasts, cells that degrade bone - precisely the type of cell they were trying to target with the agent. The chemically novel Dpp functional group localizes the drug specifically to bone tissue. Team leader thinks this will provide a safety net in terms of preventing the compd from getting into other tissues |
| UPDATE | 08.00 |
| AUTHOR | This data is not available for free |
| COMPANY | This data is not available for free |
| LITERATURE REF. | This data is not available for free |
| TRADEMARK | This data is not available for free |
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