Discovery of GPR75 small molecule ligands for the treatment of obesity

项目摘要 肥胖是一种严重的公共健康危机，其流行率在全球范围内稳步上升。超过40%的 美国的成年人肥胖，这使得肥胖管理成为一个特别重要的未得到满足的需求。肥胖 与许多并存疾病有关，如高血压、糖尿病、脂肪肝、心血管 疾病和某些类型的癌症。尽管它的流行和相关的共病，药理学 肥胖治疗的选择是有限的，特别是口服药物，这限制了 更广泛的人口。因此，开发新的口服治疗肥胖症的药物具有重要意义。 意义。从一项大规模的人类外显子组测序研究中，GPR75被鉴定为高度 与肥胖有关。截短蛋白质的GPR75基因变种被证明可以防止肥胖。 基因敲除小鼠的研究表明，对高脂肪饮食诱导的体重增加也有等位基因剂量依赖性的抵抗。 在血糖控制和胰岛素敏感性方面有好处。此外，GPR75在以下组织中表达 已知在调节能量动态平衡和新陈代谢方面发挥关键作用，包括下丘脑， 甲状腺、肝脏和脂肪组织。这些数据表明，抑制GPR75信号是一种有希望的 肥胖症管理策略。 内源性代谢产物(20-HETE)和趋化因子(CCL5)已被鉴定为GPR75配体，但 目前还没有其他有效和选择性的小分子药物候选药物的报道。在这份第一阶段提案中， 我们计划使用DNA编码文库筛选来鉴定新的小分子拮抗剂，负性 GPR75的变构调节剂和部分激动剂，并进行了实验验证。此外，我们还将 确定GPR75的非活性状态结构作为未来虚拟筛选的模板和 在第二阶段为基于结构的点击到领先的优化奠定基础。 此第一阶段提案是对编号为PA-22-176的融资机会公告(FOA)的回应 《PHS 2022-2美国国立卫生研究院、美国疾病控制与预防中心和美国食品及药物管理局小企业创新研究资助综合征集》 申请(母公司SBIR[R43/R44]不允许进行临床试验)“。

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)”.