The retinoid pathway is a central regulatory pathway in human biology that has been considered undruggable for the last 20 years. It is activated when dietary vitamin A is transported to target tissues, is oxidized to all-trans retinoic acid (atRA), and then binds the RAR?/?/? nuclear receptors. This binding results in transcriptional regulation that is best known to influence the differentiation state of various cells and tissues. In metabolic disorders, ALDH1a3 is a key enzyme responsible for the final synthetic step of the retinoid ligand, and has also been identified as one of the principal pancreatic ? cell markers for Type 2 diabetes. Numerous studies have shown that ALDH1a3 protein levels or enzymatic activity is a specific marker for failing/dedifferentiated ? cells that lose the ability to produce insulin in Type 2 diabetics. Whereas retinoid signaling has long been a pathway of interest in both rodent and human diabetes, published studies have not established whether or not retinoid signaling and thus ALDH1a3 are drivers of Type 2 diabetes. Our initial discovery work suggests that ALDH1a3 is a driver of the ? cell dedifferentiation observed in Type 2 diabetes and thus may offer a target whose inhibition can offer durable treatment effects for diabetics. Discussions with stakeholders across the Type 2 Diabetes community have demonstrated considerable interest in disease-modifying therapies that restore pancreatic function as there is broad recognition that current therapies are limited in activity to controlling blood glucose levels and insulin sensitivity rather than affecting pancreatic health. Thus, to reverse the projected rise of Type 2 diabetics across the world, next generation drug combinations are needed that restore pancreatic ? cells to their normal differentiation status. Utilizing proprietary chemistry platforms, Kayothera is the first group to have developed lead inhibitors against ALDH1a3 that show exceptional potency and specificity while avoiding the pharmacologic liabilities of other drug development programs in the retinoid pathway. Our therapies show strong potency in inhibiting the retinoid pathway (<5 nM cellular, a 200-fold improvement over published molecules), no off-target activity, high metabolic stability, excellent oral pharmacokinetic properties and promising in vivo toxicology. Here we propose to nominate an IND development candidate through dose-range finding studies and PD/efficacy models. The results of this research proposal will advance a first-in-class therapy toward clinical testing with the aim of restoring pancreatic health to millions of patients in need.
Public Health Relevance Statement: Project narrative: This project advances a novel therapy that targets a clinically important yet previously undruggable pathway that may be disease-modifying in Type 2 Diabetes. Kayothera has developed this first-in-class therapy using a next- generation drug discovery platform based on discoveries from Princeton University. Specific aims outlined in the grant will provide the basis for advancing this therapy to IND-enabling experiments through a series of pharmacokinetic and pharmacodynamic assays.
Project Terms: Achievement Attainment; Achievement; Affect; inhibitor; Biological Assay; Assay; Bioassay; Biologic Assays; Biological Availability; Bioavailability; Physiologic Availability; Blood Glucose; Blood Sugar; Cell Differentiation process; Cell Differentiation; Cells; Cell Body; Chemistry; Pharmaceutical Chemistry; Medicinal Chemistry; Pharmaceutic Chemistry; Clinical Trials; Communities; Dedications; 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; Disease; Disorder; Drug Combinations; Pharmaceutical Preparations; Drugs; Medication; Pharmaceutic Preparations; drug/agent; Enzymes; Enzyme Gene; Epidemic; Exhibits; Future; Grant; Head; Health; Human; Modern Man; Hyperlipidemia; Hyperlipemia; Insulin; Humulin R; Novolin R; Regular Insulin; Lead; Pb element; heavy metal Pb; heavy metal lead; Ligands; Metabolic Diseases; Metabolic Disorder; Thesaurismosis; metabolism disorder; oxidation; Oxidoreductase; Dehydrogenases; Oxidoreductase Gene; Reductases; Pancreas; Pancreatic; Structure of beta Cell of islet; Pancreatic beta Cell; Pancreatic ?-Cell; pancreas beta cell; pancreas ? cell; pancreatic b-cell; Legal patent; Patents; Patients; Drug Kinetics; Pharmacokinetics; Pharmacology; Program Development; Proteins; Publishing; research and development; Development and Research; R & D; R&D; Research Proposals; Retinoids; Retinoic Acid Agent; Retinoic Acid and Derivatives; Rodent; Rodentia; Rodents Mammals; Safety; Signal Transduction; Cell Communication and Signaling; Cell Signaling; Intracellular Communication and Signaling; Signal Transduction Systems; Signaling; biological signal transduction; Specificity; Testing; Tissues; Body Tissues; Toxicology; Translating; Tretinoin; ATRA; Retinoic Acid; Trans Vitamin A Acid; Tretinoinum; Vitamin A Acid; all-trans-Retinoic Acid; all-trans-Vitamin A acid; trans-Retinoic Acid; Universities; Vitamin A; Work; glucagon-like peptide 1; GLP-1; Family member; Schedule; RAR alpha; RAR-?; RARalpha; RAR?; retinoic acid receptor ?; retinoic acid receptor alpha; improved; Hepatic; Clinical; Phase; Series; Nuclear Receptors; Blood Serum; Serum; Failure; insight; Individual; diabetic; Agonist; Collaborations; Metabolic; tool; scaffold; scaffolding; Scientist; Oral; Route; restoration; interest; receptor; Receptor Protein; cell dedifferentiation; Hydrophobicity; synergism; Structure; Human Biology; novel; aldehyde dehydrogenases; ALDH; Modeling; Property; cross reactivity; drug development; Phase I Clinical Trials; Early-Stage Clinical Trials; Phase 1 Clinical Trials; phase I protocol; drug discovery; insulin sensitivity; Transcription Regulation; Transcriptional Control; Transcriptional Regulation; Molecular Interaction; Binding; Insulin Cell; Insulin Secreting Cell; ?-cell; ?-cells; ?Cell; Beta Cell; Pharmaceutical Agent; Pharmaceuticals; Pharmacological Substance; pharmaceutical; Pharmacologic Substance; insulin secretion; Dose; Affinity; Data; Regulatory Pathway; in vivo; research clinical testing; Clinical Evaluation; Clinical Testing; clinical test; therapy outcome; therapeutic outcome; Small Business Innovation Research Grant; SBIR; Small Business Innovation Research; Modification; Development; developmental; Pathway interactions; pathway; under served group; under served individual; under served people; under served population; underserved group; underserved individual; underserved people; Underserved Population; next generation; db/db mouse; Prevalence; innovate; innovative; innovation; treatment effect; 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; new drug target; new druggable target; new pharmacotherapy target; new therapy target; novel drug target; novel druggable target; novel pharmacotherapy target; novel therapeutic target; novel therapy target; new therapeutic target; pre-clinical efficacy; preclinical efficacy; candidate selection; efficacy testing; pharmacodynamic marker; pharmacodynamic biomarker; identification of biomarkers; marker identification; biomarker identification; experiment; experimental research; experiments; experimental study; lead optimization; lead candidate; secondary end point; secondary endpoint; Type II diabetic; Type 2 diabetic; PK/PD; pharmacokinetics and pharmacodynamics; early clinical trial; early phase clinical trial; dietary; marginalized population; marginalized group; marginalized individual; marginalized people; antagonist; antagonism; pharmacologic
