Nonalcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease. One-fourth of the adult population suffers from NAFLD worldwide. Nonalcoholic steatohepatitis (NASH), the aggressive form of NAFLD, can progress to cirrhosis and hepatocellular cancer (HCC) and is rapidly becoming the leading cause of end-stage liver disease and liver transplantation. Liver fibrosis is a major consequence of chronic liver disease, where the excess extracellular matrix is deposited, which is caused by the activation of hepatic stellate cells (HSCs). There is an urgent public health need to develop safe and effective pharmacological treatments to alleviate hepatic inflammation, fibrosis, and steatohepatitis. However, there are no FDA-approved medications for NAFLD. This SBIR Phase I proposal seeks to evaluate ABI-171, a novel compound with demonstrated selectivity for DYRK1A and its close family member DYRK1B in biochemical and cellular assays. ABI-171 exhibits pharmacological activity with evidence of efficacy in several animal models of disease. We hypothesize that its broad anti-inflammatory and cytoprotective activities combined with its potential health-promoting activities to thwart diabetes, reduce fatty acid uptake, and suppress collagen accumulation may effectively combat NAFLD. In this Phase I study, two specific aims are proposed: in Aim 1 we will evaluate the accumulation of ABI-171 in the organs of interest, namely the liver, to advance its safety profile. In Aim 2, we will test the efficacy of ABI-171 in the high-fat diet model of NASH, which is well-established for providing mechanistic insight of treatments and its potential for research translation. Detailed readouts for this study will be bodyweight and food intake, insulin resistance, liver injury biomarkers, liver pathology including histological and biochemical assessments, and expression levels of genes and proteins involved in DYRK1A/1B-mediated regulation of cellular cytoprotection, inflammation, lipogenesis, and fibrogenesis. The successful completion of this application will significantly advance the efficacy and mechanism of action of our selective DYRK inhibitor in NASH, thus forming strong foundation for a Phase 2 project in which drug activity will be examined in more detail for the treatment of metabolic disorders and complete the development work needed to move ABI- 171 into an early-stage clinical trial.
Public Health Relevance Statement: PROJECT NARRATIVE The proposed project will help us better understand the role of DYRK kinases and the usefulness of our small molecule inhibitor, ABI-171, in treating metabolic disorders. In addition, the proposed research is relevant to public health because this study will help identify new targets and develop new drugs to treat nonalcoholic fatty liver disease (NAFLD), an important metabolic disorder for which there is no approved treatment.
Project Terms: 21+ years old; Adult Human; adulthood; Adult; Affect; AD dementia; Alzheimer Type Dementia; Alzheimer disease dementia; Alzheimer sclerosis; Alzheimer syndrome; Alzheimer's; Alzheimers Dementia; Primary Senile Degenerative Dementia; primary degenerative dementia; senile dementia of the Alzheimer type; Alzheimer's Disease; inhibitor; Anti-Inflammatories; Anti-inflammatory; Antiinflammatories; Antiinflammatory Agents; antiinflammatory; Anti-Inflammatory Agents; Antioxidants; anti-oxidant; Attention; Biological Availability; Bioavailability; Physiologic Availability; Biological Sciences; Biologic Sciences; Bioscience; Life Sciences; Body Weight; Pharmaceutical Chemistry; Medicinal Chemistry; Pharmaceutic Chemistry; Collagen; Cyclodextrins; Cycloamylose; Cyclomaltooligosaccharides; Diabetes Mellitus; diabetes; Non-Insulin-Dependent Diabetes Mellitus; Adult-Onset Diabetes Mellitus; Ketosis-Resistant Diabetes Mellitus; Maturity-Onset Diabetes Mellitus; NIDDM; Non-Insulin Dependent Diabetes; Noninsulin Dependent Diabetes; Noninsulin Dependent Diabetes Mellitus; Slow-Onset Diabetes Mellitus; Stable Diabetes Mellitus; T2 DM; T2D; T2DM; Type 2 Diabetes Mellitus; Type 2 diabetes; Type II Diabetes Mellitus; Type II diabetes; adult onset diabetes; ketosis resistant diabetes; maturity onset diabetes; type 2 DM; type II DM; type two diabetes; Diet; diets; Animal Disease Models; Down Syndrome; Down's Syndrome; Downs Syndrome; Langdon Down syndrome; Mongolism; Trisomy 21; chromosome 21 trisomy syndrome; congenital acromicria syndrome; morbus Down; pseudohypertrophic progressive muscular dystrophy; trisomy 21 syndrome; Pharmacotherapy; Drug Therapy; drug treatment; Pharmaceutical Preparations; Drugs; Medication; Pharmaceutic Preparations; drug/agent; Eating; Food Intake; Exhibits; Extracellular Matrix; Cell-Extracellular Matrix; ECM; Fatty Acids; Fatty Liver; Liver Steatosis; hepatic steatosis; hepatosteatosis; Fibrosis; Foundations; Genes; Glial Fibrillary Acidic Protein; Astroprotein; GFA-Protein; GFAP; Glial Fibrillary Acid Protein; Glial Intermediate Filament Protein; Goals; Half-Life; Health Promotion; Salutogenesis; promoting health; Primary carcinoma of the liver cells; Hepatocarcinoma; Hepatocellular Carcinoma; Hepatocellular cancer; Hepatoma; Liver Cells Carcinoma; liver carcinoma; Hypertriglyceridemia; Hyperglyceridemia; Raised TG; Raised triglycerides; elevated tg; elevated triglyceride; high triglycerides; increased triglycerides; In Vitro; Inflammation; Insulin Resistance; insulin resistant; Interferon Type II; IFN-Gamma; IFN-g; IFN-γ; IFNG; IFNγ; Immune Interferon; Interferon Gamma; lFN-Gamma; Lead; Pb element; heavy metal Pb; heavy metal lead; Liver; hepatic body system; hepatic organ system; Liver diseases; Hepatic Disorder; hepatic disease; hepatopathy; liver disorder; liver transplantation; Hepatic Transplantation; Liver Grafting; Liver Transplant; Drug Metabolic Detoxication; Drug Metabolic Detoxification; Metabolic Drug Detoxications; Metabolism of Toxic Agents; detoxification; Metabolic Diseases; Metabolic Disorder; Thesaurismosis; metabolism disorder; Mus; Mice; Mice Mammals; Murine; nervous system disorder; Nervous System Diseases; Neurologic Disorders; Neurological Disorders; neurological disease; Obesity; adiposity; corpulence; Oxidation-Reduction; Redox; oxidation reduction reaction; Pancreas; Pancreatic; Structure of beta Cell of islet; Pancreatic beta Cell; Pancreatic β-Cell; pancreas beta cell; pancreas β cell; pancreatic b-cell; Pathology; Drug Kinetics; Pharmacokinetics; Phosphorylation; Protein Phosphorylation; Phosphotransferases; Kinases; Phosphotransferase Gene; Transphosphorylases; Plasma; Blood Plasma; Plasma Serum; Reticuloendothelial System, Serum, Plasma; Production; Proteins; Public Health; Research; Role; social role; Safety; Specificity; Testing; Time; transcription factor; Basal Transcription Factor; Basal transcription factor genes; General Transcription Factor Gene; General Transcription Factors; Transcription Factor Proto-Oncogene; Transcription factor genes; Tyrosine; Vitamin E; Work; Pioglitazone; cytokine; Measures; Enhancers; Family member; Mediating; Active Oxygen; Oxygen Radicals; Pro-Oxidants; Reactive Oxygen Species; CCND1 Protein; G1/S-Specific Cyclin D1; PRAD1 Protein; Proto-Oncogene Proteins c-bcl-1; bcl-1 Proto-Oncogene Products; bcl-1 Proto-Oncogene Proteins; bcl1 Proto-Oncogene Proteins; c-bcl-1 Proteins; cyclin D; Cyclin D1; Organ; improved; Hepatic; Peripheral; Area; Phase; Histologically; Histologic; Biochemical; NF-AT; NF-AT proteins; NFAT proteins; NFAT-1; NFATC proteins; cytoplasmic nuclear factor of activated T-cells; transcription factor NF-AT; nuclear factors of activated T-cells; Ito Cell; Hepatic Stellate Cell; Distress; insight; Hepatotoxic effect; Liver Toxicity; Toxic effect on liver cells; hepatic toxicity; hepatoxicity; Hepatotoxicity; fibrotic liver; hepatic fibrosis; Liver Fibrosis; Disease Progression; uptake; Oncology Cancer; Oncology; Collaborations; Therapeutic; Inflammatory; Deposition; Deposit; chronic liver disease; chronic hepatic disease; chronic hepatic disorder; chronic liver disorder; Oral; Route; Cytoprotection; Cell Protection; cytoprotective; interest; cell growth regulation; Cellular Regulation; Cell Proliferation; Cell Growth in Number; Cell Multiplication; Cellular Proliferation; fibrogenesis; lipid biosynthesis; adipogenesis; lipogenesis; neuroprotection; neuroprotective; nephrotoxicity; Nephrotoxic; kidney toxicity; Proxy; Toxic effect; Toxicities; novel; Drug Exposure; Modeling; response; NQO1 gene; DIA4; DT Diaphorase; DTD gene; DTD protein; Diaphorase-4; Menadione Reductase; NAD(P)H Dehydrogenase (Quinone); NAD(P)H:Menadione Oxidoreductase 1, Dioxin-Inducible 1; NMOR1; NQO1; Phylloquinone Reductase; Phase I Clinical Trials; Early-Stage Clinical Trials; Phase 1 Clinical Trials; phase I protocol; drug mechanism; Antidiabetic Drugs; Anti-diabetic Agents; Antidiabetic Agents; anti-diabetic; anti-diabetic drugs; antidiabetic; kinase inhibitor; VEGF; VEGFs; Vascular Endothelial Growth Factors; COL1A1 gene; COL1A1; FABP1 gene; FABP1; FABPL; L-FABP; Dose; Data; Molecular Target; in vivo; Cellular Assay; cell assay; Pharmacological Treatment; Small Business Innovation Research Grant; SBIR; Small Business Innovation Research; Translational Research; Translational Science; translation research; translational investigation; Tyrosine Phosphorylation; Pathologic; Development; developmental; nuclear factor-erythroid 2; NF-E2 protein; NF-E2 transcription factor; NFE2 protein; Cirrhosis; cirrhotic; safety study; Pathway interactions; pathway; neural inflammation; neuroinflammatory; neuroinflammation; Steatohepatitis; Outcome; Population; innovate; innovative; innovation; new drug treatments; new drugs; new pharmacological therapeutic; new therapeutics; new therapy; next generation therapeutics; novel drug treatments; novel drugs; novel pharmaco-therapeutic; novel pharmacological therapeutic; novel therapy; novel therapeutics; murine model; mouse model; therapeutic target; neuronal survival; NASH; non-alcohol induced steatohepatitis; non-alcoholic steato-hepatitis; non-alcoholic steatohepatitis; nonalcoholic steato-hepatitis; nonalcoholic steatohepatitis; combat; FDA approved; bio-markers; biologic marker; biomarker; Biological Markers; in vitro activity; efficacy testing; animal efficacy; Phase I Study; phase 1 study; Regimen; Drug Targeting; Injury to Liver; hepatic damage; hepatic injury; liver damage; liver injury; hepatic inflammation; inflamed liver; liver inflammation; Formulation; small molecule inhibitor; High Fat Diet; NAFLD; non-alcohol fatty liver disease; non-alcoholic liver disease; nonalcoholic fatty liver disease; non-alcoholic fatty liver disease; PK/PD; pharmacokinetics and pharmacodynamics; end stage liver disease; end stage liver failure; pharmacologic
