Development of an HTS assay to identify FXR antagonists

开发 HTS 测定法来鉴定 FXR 拮抗剂

• 批准号: 8049956
• 负责人: Thomas P Burris
• 金额: $ 19.45万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-27 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8049956
• 关键词: Address; Agonist; Bile Acids; Biochemical; Biological Assay; Biological Process; Chemicals; Cholelithiasis; Development; Diabetes Mellitus; Disease; Drug Delivery Systems; Dyslipidemias; Fatty Acids; Glucose; Homeostasis; Human; Inflammation; Ligands; Malignant Neoplasms; Metabolism; Nuclear Hormone Receptors; Nuclear Receptors; Physiological; Play; Regulation; Research; Retinoids; Role; Scheme; Screening procedure; Steroid Receptors; Thyroid Hormones; assay development; high throughput screening; lipid metabolism; member; receptor; receptor function; small molecule libraries; success; tool

DESCRIPTION (provided by applicant): Members of the human nuclear hormone receptor (NR) superfamily serve as receptors for steroids, thyroid hormones, retinoids, oxysterols, fatty acids, and bile acids. Nearly all of the NRs with identified ligands have been successful targets for drugs treating a variety of diseases including diabetes, dyslipidemia, inflammation, and cancer. FXR is a NR that functions as a physiological receptor for bile acids. FXR plays a critical role in bile acid homeostasis as well as glucose and lipid metabolism. FXR has been implicated as a drug target for the treatment of dyslipidemia (atheroscelerosis), diabetes, and gallstones. Although a few synthetic agonists have been identified for FXR, no selective antagonists have yet been characterized. Thus, the chemical tools available to characterize this receptor are limited. The proposed research is focused on development of assays to identify FXR antagonists that can be used as chemical tools to fully characterize the biological function of FXR as well as to validate this receptor as a potential drug target. In order to develop the assays required for identification of FXR antagonists the following specific aims will be addressed: (1) Develop and validate a biochemical assay to detect FXR antagonists in a high-throughput screen format.; (2) Develop and validate secondary assays for the purpose of characterizing antagonist "hits" identified in an FXR high throughput screen; and (3) Perform a validating screen of the FXR assay flow scheme using the LOPAC 1280 chemical library. PUBLIC HEALTH RELEVANCE: This proposal focuses on development of screening assays to identify specific FXR antagonists. FXR is a nuclear receptor that functions as a physiological receptor for bile acids. No selective FXR antagonists currently exist and identification of antagonists will allow for characterization of the role of this receptor in regulation of metabolism.

描述（由申请人提供）：人类核激素受体（NR）超家族的成员充当类固醇、甲状腺激素、类维生素A、氧甾醇、脂肪酸和胆汁酸的受体。几乎所有具有已确定配体的 NR 都已成为治疗多种疾病（包括糖尿病、血脂异常、炎症和癌症）的药物的成功靶标。 FXR 是一种 NR，充当胆汁酸的生理受体。 FXR 在胆汁酸稳态以及葡萄糖和脂质代谢中发挥着关键作用。 FXR 已被认为是治疗血脂异常（动脉粥样硬化）、糖尿病和胆结石的药物靶点。尽管已经鉴定出一些针对 FXR 的合成激动剂，但尚未确定选择性拮抗剂的特征。因此，可用于表征该受体的化学工具是有限的。拟议的研究重点是开发鉴定 FXR 拮抗剂的测定方法，这些拮抗剂可用作化学工具，以充分表征 FXR 的生物学功能，并验证该受体作为潜在的药物靶点。为了开发鉴定 FXR 拮抗剂所需的检测方法，将解决以下具体目标：（1）开发并验证一种生化检测方法，以高通量筛选形式检测 FXR 拮抗剂。 (2) 开发并验证二次测定，以表征 FXR 高通量筛选中识别的拮抗剂“命中”； (3) 使用 LOPAC 1280 化学库对 FXR 测定流程方案进行验证筛选。 公共健康相关性：该提案的重点是开发筛选方法来识别特定的 FXR 拮抗剂。 FXR 是一种核受体，充当胆汁酸的生理受体。目前不存在选择性 FXR 拮抗剂，拮抗剂的鉴定将允许表征该受体在代谢调节中的作用。