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Transcript
September 2006 2005 Nuclear Receptor Program Fact Sheet The nuclear receptors are a family of transcription factors which regulate a wide array of biological processes, including those involved in diabetes, obesity, cardiovascular disease and cancer. Many important therapeutics, including 12 of the top 100 selling drugs, target nuclear receptors. Plexxikon has focused discovery efforts on novel therapeutics targeting several members of the nuclear receptor family, particularly those where known small molecule modulators are limited or where the limitations of existing therapeutics provide a significant clinical opportunity. Among the company’s discovery programs, a pan compound targeting PPAR α, δ and γ for Type II diabetes and related cardiovascular disorders is most advanced at the clinical development stage. Plexxikon pursues drug discovery in nuclear receptors through a strategy to access low molecular weight chemical scaffolds that have previously not been exploited. Plexxikon’s Scaffold-Based Drug DiscoveryTM starts with screening of the company’s compound library to identify low molecular weight, low affinity compounds with activity against multiple members or isoforms of the nuclear receptor family. Structural analysis based on co-crystallography of the active compounds leads to the selection of certain compounds as scaffold candidates – those compounds which exhibit a dominant binding mode and have appropriate sites for substitution, tractable chemistry and novel intellectual property potential. In a subsequent step, Plexxikon validates candidate scaffolds by synthesizing and evaluating a small exploratory library. Such validated scaffolds can then be employed as starting points for individual discovery programs targeting specific nuclear receptors. Plexxikon Scaffold-Based Drug DiscoveryTM Process Validated scaffolds Lead discovery & Optimization for specific target Compound library screening hits (low affinity) Co-crystallography Chemical tractability Side-chain enumeration Parallel synthesis Exploratory library Biochemical assay Co-crystallography Plexxikon has applied this strategy to identify multiple novel scaffolds for PPARs. A series of novel pan-active compounds that target all three PPAR subtypes (α, γ, and δ) has been developed. In vivo PK and efficacy studies testing these lead compounds have demonstrated excellent PK properties and biological activities and represent a novel class of potential therapeutics for Type II diabetes and associated syndromes. Other nuclear receptor discovery efforts are focused on orphan receptors involved in cholesterol and bile acid metabolism (LXR, FXR, HNF4, LRH-1, SHP) and steroid synthesis (SF-1, DAX), classic endocrine receptors (VDR, TR), and steroid receptors (GR, AR). Nuclear Receptor Program Fact Sheet Selected Plexxikon Nuclear Receptor Co-Crystals Among the key strengths of Plexxikon’s platform is the capability to screen low molecular weight “scaffold-like” compounds, and to apply structural screening at an early point in lead finding. This approach addresses a key challenge in drug discovery today: how to discover novel lead compounds targeting members of a particular protein family rapidly and efficiently. By using X-ray crystallography to aid in the mining of largely unexplored chemical space, Plexxikon develops a structure-guided road map for the efficient discovery and optimization of unique compounds with remarkable bioactivity. Plexxikon is seeking to collaborate Novel LXR Scaffold GR Structure with pharmaceutical partners with strong clinical development expertise in diseases involving nuclear receptors. A collaboration may be based on a single drug target or multiple targets in a common biological pathway. In such a collaboration Plexxikon would provide novel, potent and selective lead 1.5 Å compounds as clinical candidates for further development by the partner. Phospholipids Identified As Ligands For Human SF-1 and LRH-1 L378 SF-1 L344 Y470 Y436 T377 K474 K440 G341 Wang et al. PNAS 102, 7505-10, 2005. LRH-1 Contact: Kathleen Sereda Glaub Plexxikon Inc. President Phone: 510.647.4009 Fax: 510.548.8014 [email protected] www.plexxikon.com