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

To: Hippieslayer who wrote (22928)	7/8/1998 5:16:00 PM
From: Henry Niman	Respond to of 32384

In addition to the presentation at the Signal Transduction meeting next week, LGND will be presenting next month at a high throughput screening conference and they will use the G-CSF mimic as an example of how powerful the technology is: Assays for Detecting Modulators of Cytokine Signaling Peter Lamb, Ph.D., Associate Director, Transcription Research, Ligand Pharmaceuticals Inc. The elucidation of the JAK/STAT signal transduction pathway presents new opportunities for the discovery of small molecule modulators of cytokine signaling. We have developed a number of high throughput cell-based assays capable of detecting either agonists or antagonists of these pathways. Some of the key parameters in the development and deployment of assays of this type will be described. Results obtained with a model compound illustrating translation of screening results into activity in downstream assays will also be presented.

To: Hippieslayer who wrote (22928)	7/9/1998 9:05:00 AM
From: Henry Niman	Read Replies (1) \| Respond to of 32384

Ligand will also be discussing its G-CSF mimic at a Signal Transduction meeting in San Diego in October: Discovery and Characterization of a Small Molecule Cytokine Mimic Peter Lamb, Ph.D., Associate Director, Transcription Research, Ligand Pharmaceuticals Using a cell-based screen that detects activated STATs, we at Ligand Pharmaceuticals have identified a non-peptidyl small molecule that selectively mimics a protein cytokine. This compound is active in multiple assays of cytokine activity in vitro and in vivo. The mechanism of action of the compound will be discussed. Identification of this compound provides proof of principle for drug discovery using JAK/STAT-based assays, and shows that a small non-peptidyl molecule can trigger the activation of a large protein receptor.

To: Hippieslayer who wrote (22928)	7/9/1998 9:19:00 AM
From: Henry Niman	Respond to of 32384

At a Nuclear Hormone conference in October (also in San Diego) LGND will talk about use of its various rexinoid to decode cross-talk and heterodimerization: Retinoids, the Next Generation: Gene and Dimer-Specific Rexinoids Deepak S. Lala, Ph.D., Research Scientist, Department of Retinoid Research, Ligand Pharmaceuticals Inc. RXR is considered a master receptor due to its ability to form heterodimers with other members of the nuclear receptor super-family. This talk will cover our recent work on the nuclear receptor RXR, using unique small molecule ligands to decipher novel functional properties of RXR dimers and their impact upon RXR signaling.

To: Hippieslayer who wrote (22928)	7/9/1998 9:24:00 AM
From: Henry Niman	Read Replies (2) \| Respond to of 32384

At the same conference, LGND exclusive consultant, Ron Evans, will talk about some novel ligands for PPARgamma and potential applications for atherosclerosis: Nuclear Receptors in the Genesis and Treatment of Diabetes and Atherosclerosis Ronald M. Evans, Ph.D., Investigator, Howard Hughes Medical Institute Professor, The Salk Institute for Biological Studies This talk will describe the recent studies on the characterization of ligands for the PPAR class of orphan nuclear receptors. Surprisingly, oxLDL activates PPAR[gamma] and contains two related oxidized lipids (9-HODE and 13-HODE) as novel PPAR[gamma] ligands. These results directly implicate PPAR[gamma] in macrophage/foam cell differentiation and suggest a likely role in atherogenesis.

To: Hippieslayer who wrote (22928)	7/9/1998 10:02:00 AM
From: Henry Niman	Respond to of 32384

The news about the activators of PPARgamma was reported a few months ago: Cell 1998 Apr 17;93(2):241-252 PPARgamma promotes monocyte/macrophage differentiation and uptake of oxidized LDL. Tontonoz P, Nagy L, Alvarez JG, Thomazy VA, Evans RM The Salk Institute for Biological Studies, La Jolla, California 92037, USA. The formation of foam cells from macrophages in the arterial wall is characterized by dramatic changes in lipid metabolism, including increased expression of scavenger receptors and the uptake of oxidized low-density lipoprotein (oxLDL). We demonstrate here that the nuclear receptor PPARgamma is induced in human monocytes following exposure to oxLDL and is expressed at high levels in the foam cells of atherosclerotic lesions. Ligand activation of the PPARgamma:RXRalpha heterodimer in myelomonocytic cell lines induces changes characteristic of monocytic differentiation and promotes uptake of oxLDL through transcriptional induction of the scavenger receptor CD36. These results reveal a novel signaling pathway controlling differentiation and lipid metabolism in monocytic cells, and suggest that endogenous PPARgamma ligands may be important regulators of gene expression during atherogenesis. PMID: 9568716, UI: 98227667

To: Hippieslayer who wrote (22928)	7/9/1998 10:04:00 AM
From: Henry Niman	Respond to of 32384

Here's the abstract for the companion paper on the PPARgamma natural ligands: Cell 1998 Apr 17;93(2):229-240 Oxidized LDL regulates macrophage gene expression through ligand activation of PPARgamma. Nagy L, Tontonoz P, Alvarez JG, Chen H, Evans RM The Salk Institute of Biological Studies, Howard Hughes Medical Institute, La Jolla, California 92037, USA. Macrophage uptake of oxidized low-density lipoprotein (oxLDL) is thought to play a central role in foam cell formation and the pathogenesis of atherosclerosis. We demonstrate here that oxLDL activates PPARgamma-dependent transcription through a novel signaling pathway involving scavenger receptor-mediated particle uptake. Moreover, we identify two of the major oxidized lipid components of oxLDL, 9-HODE and 13-HODE, as endogenous activators and ligands of PPARgamma. Our data suggest that the biologic effects of oxLDL are coordinated by two sets of receptors, one on the cell surface, which binds and internalizes the particle, and one in the nucleus, which is transcriptionally activated by its component lipids. These results suggest that PPARgamma may be a key regulator of foam cell gene expression. PMID: 9568715, UI: 98227666