SBIR-STTR Award

Obesity has reached epidemic proportions in the U.S. and plays a major role in the development of type 2 diabetes, dyslipidemia, and cardiovascular disease. There remains a very significant need for better non- surgical treatments. While most current weight loss agents act by suppressing appetite, strategies that can safely enhance energy expenditure have the potential to effectively treat obesity. Brown adipose tissue (BAT) is a thermogenic tissue that uniquely expresses mitochondrial UnCoupling Protein-1 (UCP1). This protein dissipates, in a regulated fashion, the electrochemical gradient in the mitochondria of brown adipocytes as heat, and thus plays an important role in the maintenance of body temperature and energy balance in rodents and humans. BAT is a flexible tissue that normally enlarges or atrophies over time depending on environmental temperature. In many different rodent models, enhancement of BAT mass has convincingly been shown to lead to weight loss and diabetes resistance. While BAT was until recently thought to be effectively nonexistent in adult humans, data obtained in the past several years show that adults in fact have significant BAT and that this tissue is functional. It has been well established that a higher amount of active BAT in individuals is strongly correlated with leanness. Cold exposure in humans leads to increased BAT formation, thermogenesis, insulin sensitivity, and lipolysis, demonstrating that BAT can be recruited and lead to metabolic benefits. Moreover, the genetic locus most tightly linked with general obesity causes defective recruitment of new brown adipocytes. Until recently no brown adipocyte stem cell had been identified. We discovered human brown adipocyte progenitor cells resident in skeletal muscle that under appropriate conditions become fully functional brown adipocytes, with high levels of UCP1 and a very high metabolic rate. These cells are a unique tool that we used to develop an assay for identifying compounds with the capacity to recruit new BAT. We recently converted this assay into high throughput format and employed it to screen 7000+ compounds. We validated the screening hits, and have selected the most promising of these based on potency, maximal activity, and the potential to create improved analogs. In the proposed work, we aim to investigate the Structure Activity Relationship of the most preferred of these compounds by purchasing and synthesizing a series of novel analogs and evaluating them in vitro. We will identify those with the highest potential for advancement based on activity and physicochemical and ADME properties. A lead compound and backup will be selected, and if this work is successful we plan to advance to PK and in vivo efficacy studies. These will be followed by lead optimization, selection of a development candidate, and generation of IND-enabling safety data.

Public Health Relevance Statement:
PROJECT NARRATIVE Obesity has reached epidemic proportions in the U.S. and globally. While most weight loss agents rely on suppressing appetite to reduce caloric intake, increasing energy expenditure is another approach to weight control. Brown adipose tissue (BAT) is a recruitable, thermogenic tissue with the capacity to utilize large amounts of fat and glucose, and which is present in reduced amounts in obese patients. We discovered a human BAT progenitor/stem cell and have used this as a tool to discover a small molecule that potently recruits new BAT cells. Here we propose to generate and test novel analogs of this molecule with improved activity and physicochemical and ADME properties that would be suitable for a development candidate, with the aim of increasing brown fat and treating obesity in patients.

Project Terms:
absorption; Acids; Adipocytes; Adult; analog; Antidiabetic Drugs; Artificial Membranes; Arts; Atrophic; Award; base; Biological Assay; Biological Availability; Body Temperature; Body Weight decreased; Brown Fat; Cardiovascular Diseases; Cell Membrane Permeability; Cells; Chemistry; Collaborations; Data; design; Desire for food; Development; Diabetes Mellitus; Dose; drug candidate; Dyslipidemias; efficacy study; energy balance; Energy Intake; Energy Metabolism; Epidemic; Evaluation; experience; Fatty acid glycerol esters; flexibility; Generations; genomic locus; Glucose; Goals; Human; human data; improved; In Vitro; in vitro activity; in vitro Assay; in vitro Bioassay; in vivo; in vivo evaluation; Individual; insulin sensitivity; Investments; Lead; lead candidate; lead optimization; Libraries; Link; lipid biosynthesis; Lipolysis; Liver; Maintenance; Measures; Mediating; Medical; Metabolic; Metabolic Diseases; metabolic rate; Metabolism; Mitochondria; mitochondrial uncoupling protein; Natural Products; Non-Insulin-Dependent Diabetes Mellitus; Normal tissue morphology; novel; Obesity; obesity treatment; Oral; Parents; Patients; Performance; Permeability; Pharmaceutical Chemistry; Pharmaceutical Preparations; pharmacophore; Phase; Physiology; Play; preservation; Probability; progenitor; programs; Property; Proteins; Provider; Publishing; recruit; Resistance; Resources; response; Rodent; Rodent Model; Role; Safety; scaffold; screening; Series; Skeletal Muscle; small molecule; Solubility; stem cells; Structure; Structure-Activity Relationship; Temperature; Testing; Thermogenesis; Thinness; Time; Tissues; tool; Toxicology; Translational Research; Translations; uncoupling protein 1; Weight maintenance regimen; Weight-Loss Drugs; Work

Obesity has reached epidemic proportions in the U.S. and plays a major role in the development of type 2diabetes, dyslipidemia, and cardiovascular disease. There remains a very significant need for better non-surgical treatments. While most current weight loss agents act by suppressing appetite, strategies that cansafely enhance energy expenditure have the potential to effectively treat obesity. Brown adipose tissue (BAT)is a thermogenic tissue that uniquely expresses mitochondrial UnCoupling Protein-1 (UCP1). This proteindissipates, in a regulated fashion, the electrochemical gradient in the mitochondria of brown adipocytes asheat, and thus plays an important role in the maintenance of body temperature and energy balance inrodents and humans. BAT is a flexible tissue that normally enlarges or atrophies over time depending onenvironmental temperature. In many different rodent models, enhancement of BAT mass has convincinglybeen shown to lead to weight loss and diabetes resistance. While BAT was until recently thought to beeffectively nonexistent in adult humans, data obtained in the past several years show that adults in fact havesignificant BAT and that this tissue is functional. It has been well established that a higher amount of activeBAT in individuals is strongly correlated with leanness. Cold exposure in humans leads to increased BATformation, thermogenesis, insulin sensitivity, and lipolysis, demonstrating that BAT can be recruited and leadto metabolic benefits. Moreover, the genetic locus most tightly linked with general obesity causes defectiverecruitment of new brown adipocytes.Until recently no brown adipocyte stem cell had been identified. We discovered human brown adipocyteprogenitor cells that under appropriate conditions become fully functional brown adipocytes, with high levelsof UCP1 and a very high metabolic rate. These cells are a unique tool that we used to develop an assay foridentifying compounds with the capacity to recruit new BAT. We recently used this assay for high throughputscreening and obtained several high quality hits with good activity, potency, and analogability. We have nowcreated a series of novel analogs of the best hits with excellent activity and desirable physicochemical andADME properties.In the proposed work, we aim to demonstrate in vivo proof of concept with this series of analogs by studyingthe compounds' pharmacokinetics and efficacy in a high quality mouse model of obesity and insulinresistance. We will also investigate the molecular mechanism of the compound series. If this work issuccessful we plan to advance to compound optimization, selection of a development candidate and backup,and generation of IND-enabling safety data.

Public Health Relevance Statement:
PROJECT NARRATIVE Obesity has reached epidemic proportions in the U.S. and globally. While most weight loss agents rely on suppressing appetite to reduce caloric intake, increasing energy expenditure is another approach to weight control. Brown adipose tissue (BAT) is a recruitable, thermogenic tissue with the capacity to utilize large amounts of fat and glucose, and which is present in reduced amounts in obese patients. We discovered a human BAT progenitor/stem cell and have used it as a tool to discover a series of small molecule compounds that potently recruit new BAT cells. Here we propose to evaluate these compounds for in vivo efficacy and characterize their molecular mechanism of action, with the aim of increasing brown fat and treating obesity in patients.

Project Terms:
<21+ years old>