The goals of this project are to develop a biomarker for MLR-1023 in order to validate Lyn kinase as a molecular target for treatment of Type II diabetes (T2D) and use the biomarker to understand the pharmacokinetic/pharmacodynamic (PK/PD) disconnect in order to optimize a dosing regimen in clinical trials. These goals will be accomplished by showing MLR-1023 target engagement and kinetics of that engagement in cells and in a translatable rodent model of T2D. Results will be translated to human clinical studies. T2D is an epidemic in the U.S. that is worsening every year. The disease affects 8.3% of Americans, a rate that some expect to double by 2025. T2D was the seventh leading cause of death in 2007 and is a leading cause of a host of other disorders, including blindness and amputations. The disease takes a massive toll on the healthcare system, having caused about $174 billion in healthcare costs in 2007 alone. Although a host of therapies have been approved by FDA for T2D, there are no safe drugs that address one of the most important pathophysiological factors of the disease: insulin receptor insensitivity. The orally active drug candidate, MLR- 1023 has potential to be such a drug. Previous studies exposed two issues that could limit successful design and execution of clinical trials, as well as understanding thosetrials' results. First, at present there is no way to monitor molecular target engagement in the clinic. This absence of a mechanism for monitoring target engagement presents challenges in validating the molecular target as a treatment for T2D. Second, MLR-1023 exhibits a short pharmacokinetic half-life but a long-lasting pharmacodynamic response in rodent models. This PK/PD disconnects produces challenges in designing an optimal dosing regimen for clinical trials. We propose developing a target-linked biomarker for MLR-1023/ Lyn kinase activation to address these issues. A biomarker will permit the full interpretation of clinical trial results by understanding the extent of the relationship between target engagement and clinical efficacy. Further, such a biomarker would be critical in validating the target as a treatment for T2D and would drive research and discovery of next-generation compounds. Second, a biomarker would supplement PK data and aid in the design of an optimal clinical dosing paradigm. Although Melior has an existing IND for MLR- 1023, these issues must be addressed to maximize the probability of success in Phase II clinical trials. The hypothesis that will be tested in these studies is that MLR-1023 elicits a long-lasting activation of Lyn kinase well after the disappearance of MLR-1023 from circulation, which leads to the long-lasting glucose lowering effect. In the proposed studies, we will conduct in vitro and in vivo experiments in order to identify MLR-1023-mediated Lyn kinase signaling events. These studies will provide data in the form of phosphorylation events of downstream substrates of Lyn kinase that in turn will provide the basis for a molecular target-linked biomarker to be used in clinical studies.
Thesaurus Terms: Address;Adipocytes;Adverse Effects;Affect;Agonist;Akt2 Gene;American;Amputation;Animals;Base;Biological Assay;Biological Markers;Blindness;Blood Circulation;Blood Glucose;Cardiovascular Risk Factor;Cause Of Death;Cells;Clinic;Clinical;Clinical Efficacy;Clinical Research;Clinical Trials;Data;Design;Diabetic;Diet;Disease;Dose;Drug Candidate;Drug Kinetics;Epidemic;Evaluation;Event;Exhibits;Fatty Acid Glycerol Esters;Fda Approved;Glucose;Goals;Half-Life;Health Care Costs;Healthcare Systems;Human;Hypertension;In Vitro;In Vivo;Insulin;Insulin Receptor;Insulin Resistance;Insulin Secretion;Insulin Sensitizing Drugs;Insulin Signaling;Kinetics;Life;Link;Liver;Longitudinal Studies;Malignant Neoplasm Of Urinary Bladder;Measurement;Mediating;Molecular Target;Monitor;Mus;Needle Biopsy Procedure;Next Generation;Non-Insulin-Dependent Diabetes Mellitus;Obesity;Patients;Peroxisome Proliferator-Activated Receptors;Pharmaceutical Preparations;Pharmacodynamics;Phase;Phase Ii Clinical Trials;Phosphorylation;Phosphotransferases;Pioglitazone;Probability;Public Health Relevance;Receptor;Receptor Activation;Regimen;Research;Research Clinical Testing;Research Study;Response;Risk;Rodent;Rodent Model;Rosiglitazone;Side;Signal Transduction;Subgroup;Success;Testing;Therapeutic;Tissues;Translating;Ulcer;Weight Gain;
