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)”.

项目摘要 肥胖是严重的公共卫生危机，其普遍存在在世界范围内稳步增长。超过40％ 美国的成年人肥胖，使肥胖管理成为一个特别重要的未满足需求。肥胖 与许多合并症有关，例如高血压，糖尿病，脂肪肝病，心血管 疾病和某些类型的癌症。尽管它流行和相关的合并症，但 肥胖管理的选项有限，尤其是口服药物，这限制了使用 更广泛的人群。因此，开发用于肥胖管理的新型口服药物很高 意义。从大规模的人类外显子组测序研究中，GPR75被确定为高度 与肥胖有关。 GPR75的蛋白质​​闭合遗传变异被证明受到保护免受肥胖的保护。 淘汰小鼠研究表明，等位基因剂量依赖于高脂饮食引起的体重增加的耐药性 作为血糖控制和胰岛素敏感性的益处。此外，GPR75在组织中表达 已知在调节能量稳态和代谢，包括下丘脑， 甲状腺，肝脏和脂肪组织。这些数据表明，抑制GPR75信号是有望 客观管理策略。 内源代谢产物（20-HETE）和趋化因子（CCL5）已被鉴定为GPR75配体，但 没有报道的其他潜力和选择性的小分子候选物。在这个阶段我的建议中， 我们计划使用DNA编码的库筛选来识别新型的小分子拮抗剂，负面 GPR75的变构调节剂和部分激动剂，并通过实验验证它们。此外，我们将 确定GPR75的无活性结构作为未来虚拟筛选的模板，并 II期基于结构的命中率优化基础。 该阶段的建议是回应资金机会公告（FOA）编号PA-22-176 “小型企业创新研究赠款的NIH，CDC和FDA的PHS 2022-2综合征集 应用程序（父级[R43/R44]临床试验不允许）。