Discovery of GPR75 small molecule ligands for the treatment of obesity

发现用于治疗肥胖的 GPR75 小分子配体

• 批准号: 10697131
• 负责人: Bingfa Sun
• 金额: $ 30.34万
• 依托单位: CONFOMETRX, INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10697131
• 关键词: Adipose tissue; Adult; Agonist; Alleles; Animal Model; Applications Grants; Biological Assay; Cardiovascular Diseases; Chemicals; Clinical Trials; Country; Cryoelectron Microscopy; DNA; Data; Diabetes Mellitus; Dose; Foundations; Funding Opportunities; Future; G-Protein-Coupled Receptors; GIPR gene; GPR75 gene; High Fat Diet; Homeostasis; Human; Human Genome; Hydroxyeicosatetraenoic Acids; Hypertension; Hypothalamic structure; Knockout Mice; Libraries; Ligand Binding; Ligands; Literature; Liver; Medical Care Costs; Metabolism; Modeling; Obesity; Operative Surgical Procedures; Oral; Parents; Pharmaceutical Preparations; Phase; Population; Prevalence; Protein Truncation; Public Health; RANTES; Reporting; Resistance; Resolution; Role; Sampling; Signal Transduction; Small Business Innovation Research Grant; Structure; Study models; Subcutaneous Injections; Therapeutic; Thyroid Gland; Tissues; United States; United States National Institutes of Health; Weight Gain; antagonist; cancer type; chemokine; comorbidity; drug candidate; exome sequencing; experimental study; fatty liver disease; genetic variant; genome-wide analysis; glycemic control; insulin sensitivity; lead optimization; novel; obesity management; obesity treatment; pharmacologic; response; screening; side effect; small molecule; therapeutic candidate; tool; virtual screening

Project Summary Obesity is a serious public health crisis and its prevalence is steadily growing around the world. Over 40% of adults in the United States are obese, making obesity management a particular important unmet need. Obesity is associated with many co-morbidities, such as hypertension, diabetes, fatty liver disease, cardiovascular disease, and certain types of cancers. Despite its prevalence and associated co-morbidities, pharmacological options for obesity management are limited, especially orally available medications, which limit the usage in wider populations. Therefore, developing novel, orally available medications for obesity management is of high significance. From a large-scale human exome sequencing study, GPR75 was identified to be highly associated with obesity. Protein-truncating genetic variant of GPR75 were shown to be protected from obesity. Knock-out mice studies showed allele-dose dependent resistance to high-fat diet induced weight gain, as well as benefits in glycemic control and insulin sensitivity. In addition, GPR75 is expressed in tissues that are known to have a critical role in regulating energy homeostasis and metabolism, including the hypothalamus, thyroid gland, liver and adipose tissue. These data suggest that inhibiting GPR75 signaling is a promising strategy for obesity management. An endogenous metabolite (20-HETE) and a chemokine (CCL5) have been identified as GPR75 ligands, but there are no additional potent and selective small molecule drug candidates reported. In this Phase I proposal, we plan to use a DNA-encoded library screening to identify novel small molecule antagonists, negative allosteric modulators and partial agonists of GPR75, and verify them experimentally. In addition, we will determine the inactive-state structure of GPR75 as a template for future virtual screening and as the foundation for structure-based hit-to-lead optimization in Phase II. This Phase I proposal is in response to Funding Opportunity Announcement (FOA) Number PA-22-176 entitled “PHS 2022-2 Omnibus Solicitation of the NIH, CDC and FDA for Small Business Innovation Research Grant Applications (Parent SBIR [R43/R44] Clinical Trial Not Allowed)”.

项目概要 肥胖是一种严重的公共卫生危机，其患病率在全球范围内稳步增长，超过 40%。 美国成年人肥胖，这使得肥胖管理成为一个特别重要的未满足的需求。 与许多并发症有关，如高血压、糖尿病、脂肪肝、心血管疾病等 疾病和某些类型的癌症，尽管其患病率和相关的并发症，药理学。 肥胖管理的选择有限，特别是口服药物，这限制了其使用 因此，开发新型口服药物来控制肥胖具有重要意义。 从大规模人类外显子组测序研究中，GPR75被鉴定为高度重要。 研究表明，GPR75 的蛋白质截短基因变体可以防止肥胖。 基因敲除小鼠研究表明，对高脂肪饮食引起的体重增加具有等位基因剂量依赖性抵抗力 此外，GPR75 在以下组织中表达。 已知在调节能量稳态和新陈代谢（包括下丘脑）方面具有关键作用， 这些数据表明抑制 GPR75 信号传导是一种有前途的方法。 肥胖管理策略。 内源代谢物 (20-HETE) 和趋化因子 (CCL5) 已被确定为 GPR75 配体，但是 在这一阶段的提案中，没有报告其他有效的、选择性的小分子候选药物。 我们计划使用DNA编码库筛选来鉴定新型小分子拮抗剂，阴性 GPR75的变构调节剂和部分激动剂，并通过实验验证它们。 确定 GPR75 的非活性状态结构作为未来虚拟筛选的模板并作为 为第二阶段基于结构的命中先导优化奠定了基础。 此第一阶段提案是对编号 PA-22-176 的资助机会公告 (FOA) 的回应，题为 “PHS 2022-2 NIH、CDC 和 FDA 小型企业创新研究补助金综合征集 申请（不允许母公司 SBIR [R43/R44] 临床试验）”。