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Biotech / Medical : Ligand (LGND) Breakout! -- Ignore unavailable to you. Want to Upgrade?

To: Flagrante Delictu who wrote (22995)	7/9/1998 5:58:00 PM
From: WTDEC	Read Replies (1) \| Respond to of 32384

Important LGND news item: biz.yahoo.com

To: Flagrante Delictu who wrote (22995)	7/9/1998 5:59:00 PM
From: WTDEC	Respond to of 32384

-------------------------------------------------------------------------------- Thursday July 9, 5:23 pm Eastern Time Company Press Release Ligand and SmithKline Beecham Scientists Report First Discovery of Small Molecule G-CSF Mimic in "Science" Could Lead to Oral Therapy to Prevent Infections That Frequently Follow Cancer Chemotherapy SAN DIEGO--(BW HealthWire)--July 9, 1998-- Researchers at Ligand (LYE-gand) Pharmaceuticals (NASDAQ:LGND - news) and SmithKline Beecham (NYSE:SBH - news) have discovered the first non-peptide small molecule that mimics the biological activity of Granulocyte-Colony Stimulating Factor (G-CSF), the natural hormone that stimulates the bone marrow to produce infection-fighting neutrophils (a type of white blood cell). The discovery could lead to an oral therapy to prevent infections that frequently follow chemotherapy. The research was conducted under a collaborative research agreement and the results appear in the July 10 issue of the journal ''Science.'' ''This is the first reported discovery of a small, non-peptide molecule that exerts the same in vivo effect as a cytokine,'' said Jonathan Rosen, Ph.D., Ligand senior director, Transcription Research. ''Although activity for this particular compound has so far only been observed in murine systems, this discovery provides an important proof of concept and opens up the possibility for the development of orally active, small molecule mimics for G-CSF and for other cytokines.'' Many cancer patients receiving chemotherapy experience a serious drop in neutrophil counts and, as a result, are at increased risk of infection and death. Low white blood cell counts can also lead to chemotherapy dose reductions and interruptions in therapy. To combat these effects, patients receiving chemotherapy are often given injections of a recombinant protein form of G-CSF, to stimulate neutrophil production. Ligand and SB scientists found that their small molecule G-CSF mimic was effective in stimulating neutrophil production in a mouse model. Small molecule, orally available mimics of cytokines could have significant benefits over the currently available injectable forms; they could potentially improve patients' quality of life by eliminating the need for injectable therapies. Other injectable cytokines in current therapeutic use that would be highly amenable to similar drug discovery approaches include erythropoietin, interferons and growth hormone, among many others. Ligand is currently pursuing additional cytokine targets, including hematopoietic growth factors and leptin with SB and interferon-alpha and other immunomodulatory targets internally. ''This breakthrough research demonstrates that there now seems to be no theoretical barrier to the discovery of small molecules that would supplant the need to inject active proteins for various clinical purposes,'' said Dr. James Darnell, Vincent Astor Professor at Rockefeller University, in whose laboratory the basis of cytokine-stimulated transcription was discovered. ''This research has benefited from our knowledge of how cytokines stimulate gene transcription.'' JAKs & STATs: The Science Behind The Breakthrough The effects of G-CSF in the body are mediated by a specific receptor present on the surface of a subset of bone marrow cells. The binding of G-CSF to its receptor is the first step in the chain of events that leads to alterations in the expression of genes in the cell nucleus, and ultimately to the production of mature neutrophils. This process, which links cytokine binding to changes in gene expression, is called signal transduction. A cytokine is a member of a family of proteins released by cells that modulate the growth and function of other cells, particularly those in the immune and hematopoietic systems. When cytokines bind on the cell surface, the binding triggers biochemical responses inside the cell involving several families of proteins, including the JAKs (Janus kinases) and the STATs (signal transducers and activators of transcription). The JAKs associate with the portion of the G-CSF receptor that is inside the cell, and become activated when G-CSF binds to the receptor outside the cell. Activated JAKs then trigger the activation of specific STATs and other critical transcription factor pathways. Once activated, the STATs can migrate into the cell nucleus and alter the expression of genes involved in the production of white blood cells. By determining the ability of compounds to activate a STAT-responsive gene in G-CSF responsive cells, investigators from the Ligand/SB team were able to discover low molecular weight compounds capable of activating G-CSF signal transduction. The efficacy of these small molecule G-CSF mimics was then assessed in additional in vitro assays and in a mouse model of G-CSF action. They found that the small molecule G-CSF mimic reported in the ''Science'' article elicited an increase in active STAT levels in murine cells in vitro, and an increase in neutrophil levels in mice. Ligand and SB Collaboration Ligand and SB formed an alliance in February 1995 to discover and characterize small molecule, orally bioavailable drugs to control hematopoiesis (formation and development of blood cells). In March 1998, the companies established a new collaboration to develop small molecule drugs that modulate the signaling pathway controlled by leptin as a means of discovering orally available drugs for treatment or prevention of obesity. Since 1989, Ligand Pharmaceuticals Incorporated has established a leadership position in gene transcription technology, particularly intracellular receptor (IR) technology and STATs. Ligand has applied IR and STATs technology to the discovery and development of small molecule drugs to enhance therapeutic and safety profiles and to address unmet patient needs in cancer, women's and men's health and skin diseases, as well as osteoporosis, metabolic, cardiovascular and inflammatory diseases. This news release may contain certain forward looking statements by Ligand and actual results could differ materially from those described as a result of factors including, but not limited to, the following. There can be no assurance that results achieved in animal models will be supportive of regulatory filings required to initiate human clinical trials, that any product in the Ligand pipeline will be successfully developed, that regulatory approvals will be granted, that patient and physician acceptance of these products will be achieved, that final results of human clinical trials will be consistent with any interim results, or that final results will be supportive of regulatory approvals required to market products. Ligand undertakes no obligation to update the statements contained in this press release after the date hereof. Ligand Pharmaceuticals' releases are available via fax at no charge by calling 888/329-9832 or on the World Wide Web at www.businesswire.com/cnn/lgnd.htm. --------------------------------------------------------------------------------