On 19, June I emailed Ariad with questions regarding drug specificity (see posts 119, 121-124). Yesterday I received the following reply:
(Note- 1. There are references to 'src', 'lck', etc. and other jargon which I'll explain to those interested. 2. As part of my inquiry, I expressed concern about interaction with 'STAT' proteins. These are ubiquitous, intercellular proteins which are fundamental for an immune response (among other roles) and they contain SH2/SH3 sequences crucial for their activity.)
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subject: SH2-directed drugs
Date: Fri, 20 Jun 1997 09:21:33 -0400
From: Michael Gilman <gilman@ariad.com>
Peter:
Obviously, you raise a critical issue, namely our ability to target individual SH2 domains in a selective fashion.
As you know, there is a significant degree of sequence diversity among SH2 domains, and most importantly, ample experimental evidence that the natural ligand specificities (i.e., the peptide sequences they select) of individual SH2 domains can be quite different. These differences are easy to recapitulate with small-molecule nonpeptide ligands.
The real challenge, though, is distinguishing between very closely related domains. In our osteoporosis program, for example, we need compounds that distinguish our target protein Src from its most closely related cousins, Fyn, Yes, and, to a lesser degree, Lck. The degree of sequence similarity among these SH2 domains is quite high and their specificity for peptide ligands is nearly indistinguishable. Here the key is to identify amino acid differences between the proteins that lie within or near the binding pockets and essentially build out our compounds to interact with these side chains (either productively in Src or nonproductively in the nontarget proteins). This is where having structures really helps. And I'm pleased to say that we've done it. Distinguishing Src from Fyn and Yes is probably the most stringent test of this idea, so I'm now convinced that we ought to be able to do this for any SH2 domain.
As for STATs, we are quite interested, for obvious reasons. One is that there is already experimental evidence that SH2 ligands can both block Stat activation (by preventing recruitment to activated receptors) and kill active Stat proteins (by dissociating dimers). The challenge with Stats is that their SH2 domains are apparently nonstandard. They are very difficult to express and no one has yet reported a Stat SH2 domain structure or any studies of ligand specificity. Anyhow, we are working on it.
I hope I've been able to answer your questions. Thanks for your interest in our programs.
Yours sincerely,
Michael Gilman
Executive Vice President
Chief Scientific Officer
Tel 617-494-0400, ext. 218
Fax 617-494-1828
gilman@ariad.com
ARIAD Pharmaceuticals
26 Landsdowne St.
Cambridge, MA 02139 |
