R44DK127880

New generation of mitochondrial uncouplers for the treatment of metabolic disorders - Summary

Effective treatments for obesity have been a major need for decades, as the high prevalence of obesity and associated metabolic disorders has continued to rise.

To achieve weight loss, obesity treatments must either decrease energy intake or increase energy expenditure.

GLP-1 receptor agonists have recently emerged as the first effective drugs that decrease energy intake by reducing appetite.

While these drugs are promising, the need for alternative and complementary treatments persists due to reported variations in their efficacy and suboptimal effects on body composition.

Equator Therapeutics is developing a first-in-class drug to increase energy expenditure.

Specialized thermogenic reactions within mitochondria form the only known energy expenditure pathway that can be safely controlled without negatively impacting other essential physiological processes.

Mitochondrial thermogenesis depends on H+ leak across the inner mitochondrial membrane mediated by mitochondrial uncoupling proteins (UCPs).

In vivo, UCPs are activated by long-chain fatty acids (LCFAs).

In humans, skeletal muscle plays a dominant role in adaptive non-shivering thermogenesis.

The UCP responsible for mitochondrial thermogenesis in skeletal muscle and its pharmacological control long remained elusive until Equator’s scientific co-founders developed a method to directly measure mitochondrial H+ leak using the patch-clamp technique and demonstrated that the LCFA-induced H+ leak in skeletal muscle is mediated by the mitochondrial ADP/ATP carrier (AAC) (Bertholet et al, Nature 2019).

They also identified likely AAC binding sites for LCFAs and small-molecule activators of H+ leak (Bertholet et al, Nature 2022).

Based on this work, we are developing small-molecule activators of H+ leak via AAC that mimic the thermogenic effect of LCFAs but offer high oral bioavailability.

In the Phase 1 SBIR, we developed a high-throughput drug discovery funnel and identified four chemically unique lead molecules that selectively activate H+ leak via AAC.

We also demonstrated that one of our partially optimized compounds can increase energy expenditure and cause weight loss in diet-induced obesity (DIO) mice.

In this Phase 2 application, we propose to carry out further medicinal chemistry optimization of these lead compounds and to test optimized analogs for efficacy and safety in DIO rodent models.

The proposal has three specific aims.

In Aim 1 we will optimize our compounds to increase in vivo potency and maintain good exposures with chronic dosing.

The optimized lead compounds will then be advanced to in vivo efficacy studies in Aim 2, where we will demonstrate that they increase the metabolic rate in DIO rodent models and determine safe doses for use in subsequent weight-loss studies.

Finally, in Aim 3, we will determine the efficacy of the optimized lead compounds for treating obesity, type 2 diabetes, and fatty liver disease in DIO rodents.

Successful completion of this proposal will demonstrate efficacy of our compounds in disease models and assess potential liabilities in preparation for IND-enabling studies.

Equator Therapeutics

(1) TO PROMOTE EXTRAMURAL BASIC AND CLINICAL BIOMEDICAL RESEARCH THAT IMPROVES THE UNDERSTANDING OF THE MECHANISMS UNDERLYING DISEASE AND LEADS TO IMPROVED PREVENTIONS, DIAGNOSIS, AND TREATMENT OF DIABETES, DIGESTIVE, AND KIDNEY DISEASES. PROGRAMMATIC AREAS WITHIN THE NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES INCLUDE DIABETES, DIGESTIVE, ENDOCRINE, HEMATOLOGIC, LIVER, METABOLIC, NEPHROLOGIC, NUTRITION, OBESITY, AND UROLOGIC DISEASES. SPECIFIC PROGRAMS AREAS OF INTEREST INCLUDE THE FOLLOWING: (A) FOR DIABETES, ENDOCRINE, AND METABOLIC DISEASES AREAS: FUNDAMENTAL AND CLINICAL STUDIES INCLUDING THE ETIOLOGY, PATHOGENESIS, PREVENTION, DIAGNOSIS, TREATMENT AND CURE OF DIABETES MELLITUS AND ITS COMPLICATIONS, NORMAL AND ABNORMAL FUNCTION OF THE PITUITARY, THYROID, PARATHYROID, ADRENAL, AND OTHER HORMONE SECRETING GLANDS, HORMONAL REGULATION OF BONE, ADIPOSE TISSUE, AND LIVER, ON FUNDAMENTAL ASPECTS OF SIGNAL TRANSDUCTION, INCLUDING THE ACTION OF HORMONES, COREGULATORS, AND CHROMATIN REMODELING PROTEINS, HORMONE BIOSYNTHESIS, SECRETION, METABOLISM, AND BINDING, AND ON HORMONAL REGULATION OF GENE EXPRESSION AND THE ROLE(S) OF SELECTIVE RECEPTOR MODULATORS AS PARTIAL AGONISTS OR ANTAGONISTS OF HORMONE ACTION, AND FUNDAMENTAL STUDIES RELEVANT TO METABOLIC DISORDERS INCLUDING MEMBRANE STRUCTURE, FUNCTION, AND TRANSPORT PHENOMENA AND ENZYME BIOSYNTHESIS, AND BASIC AND CLINICAL STUDIES ON THE ETIOLOGY, PATHOGENESIS, PREVENTION, AND TREATMENT OF INHERITED METABOLIC DISORDERS (SUCH AS CYSTIC FIBROSIS). (B) FOR DIGESTIVE DISEASE AND NUTRITION AREAS: GENETICS AND GENOMICS OF THE GI TRACT AND ITS DISEASES, GENETICS AND GENOMICS OF LIVER/PANCREAS AND DISEASES, GENETICS AND GENOMICS OF NUTRITION, GENETICS AND GENOMICS OF OBESITY, BARIATRIC SURGERY, CLINICAL NUTRITION RESEARCH, CLINICAL OBESITY RESEARCH, COMPLICATIONS OF CHRONIC LIVER DISEASE, FATTY LIVER DISEASE, GENETIC LIVER DISEASE, HIV AND LIVER, CELL INJURY, REPAIR, FIBROSIS AND INFLAMMATION IN THE LIVER, LIVER CANCER, LIVER TRANSPLANTATION, PEDIATRIC LIVER DISEASE, VIRAL HEPATITIS AND INFECTIOUS DISEASES, GASTROINTESTINAL AND NUTRITION EFFECTS OF AIDS, GASTROINTESTINAL MUCOSAL AND IMMUNOLOGY, GASTROINTESTINAL MOTILITY, BASIC NEUROGASTROENTEROLOGY, GASTROINTESTINAL DEVELOPMENT, GASTROINTESTINAL EPITHELIAL BIOLOGY, GASTROINTESTINAL INFLAMMATION, DIGESTIVE DISEASES EPIDEMIOLOGY AND DATA SYSTEMS, NUTRITIONAL EPIDEMIOLOGY AND DATA SYSTEMS, AUTOIMMUNE LIVER DISEASE, BILE, BILIRUBIN AND CHOLESTASIS, BIOENGINEERING AND BIOTECHNOLOGY RELATED TO DIGESTIVE DISEASES, LIVER, NUTRITION AND OBESITY, CELL AND MOLECULAR BIOLOGY OF THE LIVER, DEVELOPMENTAL BIOLOGY AND REGENERATION, DRUG-INDUCED LIVER DISEASE, GALLBLADDER DISEASE AND BILIARY DISEASES, EXOCRINE PANCREAS BIOLOGY AND DISEASES, GASTROINTESTINAL NEUROENDOCRINOLOGY, GASTROINTESTINAL TRANSPORT AND ABSORPTION, NUTRIENT METABOLISM, PEDIATRIC CLINICAL OBESITY, CLINICAL TRIALS IN DIGESTIVE DISEASES, LIVER CLINICAL TRIALS, OBESITY PREVENTION AND TREATMENT, AND OBESITY AND EATING DISORDERS. (C) FOR KIDNEY, UROLOGIC AND HEMATOLOGIC DISEASES AREAS: STUDIES OF THE DEVELOPMENT, PHYSIOLOGY, AND CELL BIOLOGY OF THE KIDNEY, PATHOPHYSIOLOGY OF THE KIDNEY, GENETICS OF KIDNEY DISORDERS, IMMUNE MECHANISMS OF KIDNEY DISEASE, KIDNEY DISEASE AS A COMPLICATION OF DIABETES, EFFECTS OF DRUGS, NEPHROTOXINS AND ENVIRONMENTAL TOXINS ON THE KIDNEY, MECHANISMS OF KIDNEY INJURY REPAIR, IMPROVED DIAGNOSIS, PREVENTION AND TREATMENT OF CHRONIC KIDNEY DISEASE AND END-STAGE RENAL DISEASE, IMPROVED APPROACHES TO MAINTENANCE DIALYSIS THERAPIES, BASIC STUDIES OF LOWER URINARY TRACT CELL BIOLOGY, DEVELOPMENT, PHYSIOLOGY, AND PATHOPHYSIOLOGY, CLINICAL STUDIES OF BLADDER DYSFUNCTION, INCONTINENCE, PYELONEPHRITIS, INTERSTITIAL CYSTITIS, BENIGN PROSTATIC HYPERPLASIA, UROLITHIASIS, AND VESICOURETERAL REFLUX, DEVELOPMENT OF NOVEL DIAGNOSTIC TOOLS AND IMPROVED THERAPIES, INCLUDING TISSUE ENGINEERING STRATEGIES, FOR UROLOGIC DISORDERS,RESEARCH ON HEMATOPOIETIC CELL DIFFERENTIATION, METABOLISM OF IRON OVERLOAD AND DEFICIENCY, STRUCTURE, BIOSYNTHESIS AND GENETIC REGULATION OF HEMOGLOBIN, AS WELL AS RESEARCH ON THE ETIOLOGY, PATHOGENESIS, AND THERAPEUTIC MODALITIES FOR THE ANEMIA OF INFLAMMATION AND CHRONIC DISEASES. (2) TO ENCOURAGE BASIC AND CLINICAL RESEARCH TRAINING AND CAREER DEVELOPMENT OF SCIENTISTS DURING THE EARLY STAGES OF THEIR CAREERS. THE RUTH L. KIRSCHSTEIN NATIONAL RESEARCH SERVICE AWARD (NRSA) FUNDS BASIC AND CLINICAL RESEARCH TRAINING, SUPPORT FOR CAREER DEVELOPMENT, AND THE TRANSITION FROM POSTDOCTORAL BIOMEDICAL RESEARCH TRAINING TO INDEPENDENT RESEARCH RELATED TO DIABETES, DIGESTIVE, ENDOCRINE, HEMATOLOGIC, LIVER, METABOLIC, NEPHROLOGIC, NUTRITION, OBESITY, AND UROLOGIC DISEASES. (3) TO EXPAND AND IMPROVE THE SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM. THE SBIR PROGRAM AIMS TO INCREASE AND FACILITATE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO ENHANCE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. (4) TO UTILIZE THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM. THE STTR PROGRAM INTENDS TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.847 - Diabetes, Digestive, and Kidney Diseases Extramural Research

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [HHS - NIH]

Saint Louis, Missouri 631101110 United States

Single Zip Code

PHS 2023-2 Omnibus Solicitation of the NIH, CDC and FDA for Small Business Innovation Research Grant Applications (Parent SBIR [R43/R44] Clinical Trial Not Allowed) (PA-23-230)

Amendment Since initial award the total obligations have increased 100% from $1,571,137 to $3,142,274.