The small molecule mimics the natural cytokine by extracellular action at the the receptor and in that way it activates the normal signalling pathway. This advance is as much theoretical as it is practical. It provides evidence to document that small molecules can be effective agonists (as well as antagonists, though no data to my knowledge has come forward). Now, comes the next challenge. Can these compounds be generated without toxicology side effects, and can they be made with appropriate pharmacokinetic profiles. There will now be much effort in this arena, not only by LGND/SBH, but also by other pharmas. It will result in a feeding frenzy like that had happened with the Mike Snider/John Lowe advance at PFE when they reported a nonpeptide G-protein coupled receptor antagonist for peptide receptors. They proved that it could be done, but they will not be the first to the clinic with their NK-1 antagonist. MRK will. So, you see, now that the advance has been publicized, there will be mucho competition.
It will be interesting to compare LGND with AMGN during the early days of the stock rise of the latter. Amgn had a protein therapeutic that had efficacy (EPO), and the path through the clinic was easier than that with a small molecule. For LGND, there will be several more complicated development issues. Recall that the first nonpeptide antagonist for peptide receptors was discovered in 1989 or 1990, and it is still not in the clinic but is close. This is 8 years later, and there now have ben second and third generation compounds. The endpoint for this class of compounds is not as obvious as that for cytokine agonists, however. |
