Discovery of GPR75 small molecule ligands for the treatment of obesity

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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)”.