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Biotech / Medical : ARIAD Pharmaceuticals -- Ignore unavailable to you. Want to Upgrade?

To: Mike McFarland who wrote (684)	9/9/1999 10:45:00 AM
From: Mike McFarland	Read Replies (1) \| Respond to of 4474

The abstract to the SAR Src SH2 paper is here... siliconinvestor.com And I thought the summary from the Ariad patent early last year is a good one to have in front of you-- especially for bionewbies trying to go through the chapter on signal transduction (that's me). This is from patent 5,710,129 January 20, 1998 Inhibitors of SH2-mediated processes Inventors: Lynch; Berkley A. (Cambridge, MA); Weigele; Manfred (Cambridge, MA) Assignee: Ariad Pharmaceuticals, Inc. (Cambridge, MA) "One aspect of cellular function in both normal and disease states which has attracted increasing attention is cellular signal transduction, the series of events leading from extracellular events to intracellular sequelae. Numerous proteins that function as signal transducing molecules have been identified. These include receptor and non-receptor tyrosine kinases, phosphatases and other molecules with enzymatic or regulatory activities. A common feature of many of these molecules is their capacity to associate specifically with other proteins to form a signaling complex that can alter cell activity. Signaling proteins often contain one or more domains of conserved sequence which serve as non-catalytic modules that direct protein-protein interactions during signal transduction. One such domain has been termed the src homology domain 2 (SH2) domain. SH2 domains are relatively small (.about.100 amino acids for SH2) and are found in various combinations and locations in different proteins. Many proteins which contain one or more SH2 domains are already known, including the fps/fes family of protein tyrosine kinases (PTKs), ISGF3alpha p113, p91/84, Tensin, shc; syk, zap, PTPase 1C and PTPase 2; src and the src family of PTKs, abl and the abl family of PTKs, csk, tec; PLCgamma 1 and 2, GAP, p85alpha and p85 beta; vav, c-crk and GRB2; and nck. Aspects of the structures of some SH2 domains are known and certain aspects of their role in signal transduction is becoming better understood. SH2 domains direct the association of specific proteins by binding selectively and with specificity to protein sequences containing phosphotyrosine. For example, upon binding of PDGF to the PDGF .beta.-receptor, the receptor dimerizes and autophosphorylates multiple tyrosine residues. This phosphorylation triggers the physical association of SH2-containing proteins such as c-src, PLC-gamma, PI3K and ras-GAP with the receptor, forming a signaling complex. An analysis of SH2 binding using natural ligands containing mutations at residues surrounding the site of phosphorylation as well as a screen of combinatorial peptide libraries using SH2 domains has provided data on phosphopeptide sequence specificity of SH2 binding. Pharmaceutical agents which interfere with the formation or stability of signaling complexes formed by proteins containing one or more SH2 domains and their natural ligands could be used to treat or prevent the diseases or their pathological effects mediated by such complexes. Unfortunately, while phosphotyrosine has been considered a required component of an SH2 binding compound, in view of pharmacokinetic and drug delivery issues, agents other than phosphorylated tyrosine-containing oligopeptides would be particularly desirable. ----- If any traders stumble on this stuff, don't rush out and buy into ARIA thinking this SH2 stuff is anything new, wait for a press release which says ZAP! for that, heheh. This is a situation where I feel pretty confident that it's undervalued, especially when you look at AVGN's marketcap--but all I'm doing is passing the time, trying to learn a bit more about the science behind Ariad.