It is estimated that more than 5 million people in the U.S. have Alzheimer's disease (AD). The cardinal features of AD brain pathology are accumulation of A? in insoluble plaques, hyperphosphorylation of tau leading to its intracellular aggregation and as a consequence of one or both, neuronal dysfunction. Currently, no disease modifying drugs exist for AD. Jun N-terminal kinases (JNKs) are activated by most cellular stressors including A? and in in vitro models cause A?-dependent neurodegeneration. Additionally JNK has been implicated in regulating A? production and acting as a tau kinase. Thus unlike most other therapeutic approaches, there are potentially three mechanisms by which JNK inhibitors could affect the key pathological features of AD and potentially ameliorate the observed functional deficits. Treatment with a JNK inhibitor could result in a reduction in the neuronal dysfunction seen in AD patients when administered alone or possibly in combination with an anti-A? or anti-tau treatment. Imago Pharmaceuticals, Inc. (Imago) is focused on developing drug candidates targeting the JNKs. Imago is in the unique position of having acquired an advanced lead series of small molecules targeting JNKs. Unlike other JNK compounds that have been or are in development, Imago's JNK inhibitors have the unique combination of being active in vivo, possess good DMPK-properties, exhibit excellent kinome specificity, have clean in vitro and in vivo toxicological profiles and are covered by extensive patent protection. These compounds are structurally unique compared to typical kinase active site inhibitors, which has led to the elimination of the liabilities that have plagued other JNK compounds. IGP001 was nominated as a lead candidate since it possessed these exceptional drug-like properties. The studies proposed in this grant will further the development of these JNK inhibitors as an AD therapeutic. We propose testing IGP001 in a P301S tau transgenic model to determine whether IGP001 can ameliorate the behavioral deficits and alterations in long-term potentiation (LTP), decrease neurodegeneration, decrease mouse A? levels or reduce hyperphosphorylation/aggregation of tau. Our initial data, together with substantial evidence from the literature, suggest that IGP001 will improve neuronal function, and lower A? levels and hyperphosphorylation of tau. Upon successful completion of these aims, we will have demonstrated that IGP001is highly effective in reducing the functional and histopathological alterations observed in this AD model. This data will allow nomination of IGP001 as an AD drug candidate and for the program to progress into preclinical drug development studies in preparation of an investigational new drug (IND) application for the use of this JNK compound for a disease-modifying treatment for AD.
Public Health Relevance Statement: Project Narrative Alzheimer's disease (AD) is defined by the presence of large deposits of two proteins - A? and tau - in the brain, and accompanied by profound loss of the neurons in a region of the brain that helps one remember, think and independently perform daily activities. Imago Pharmaceuticals has potential drugs targeting a family of proteins, the JNKs, that could slow or inhibit neuronal loss and possibly also reduce the A? and/or tau deposits. If successful, Imago's drug could slow or eliminate AD patients' loss of memory and decline in cognitive abilities.
Project Terms: abeta accumulation; Abeta synthesis; Achievement; Active Sites; Affect; Alzheimer's Disease; Alzheimer's disease model; Amyloid beta-Protein; Animal Model; Antibodies; Astrocytosis; Autoimmune Diseases; Behavior; Behavioral; Brain; Brain Pathology; Brain region; Clinical; clinical candidate; clinical development; cognitive ability; Data; Deposition; Development; Disease; Disease Progression; drug candidate; Drug Kinetics; Drug Targeting; efficacy study; Exhibits; Family; Fibrosis; Functional disorder; good laboratory practice; Grant; Hindlimb; Hippocampus (Brain); Histologic; improved; In Vitro; in vitro Model; in vivo; in vivo Model; Inflammatory; inhibitor/antagonist; Investigational Drugs; Investigational New Drug Application; kinase inhibitor; Knock-out; Lead; lead series; Legal patent; Life; Literature; Long-Term Potentiation; Measures; Memory Loss; Modeling; morris water maze; Mus; N-terminal; Nerve Degeneration; Neurodegenerative Disorders; neuron loss; Neuronal Dysfunction; Neurons; Non-Insulin-Dependent Diabetes Mellitus; nonhuman primate; Oral; Pathologic; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacologic Substance; Phase; Phosphotransferases; Plasma; Positioning Attribute; Preclinical Drug Development; preclinical study; Preparation; programs; Property; Protein Family; Proteins; Rattus; Safety; Series; Slice; Small Business Innovation Research Grant; small molecule; small molecule inhibitor; Specificity; Staining method; Stains; Stress; stressor; tau aggregation; tau phosphorylation; tau Proteins; tau-protein kinase; Testing; Therapeutic; Toxicology; Transgenic Model; Weight
