Evaluate Efficacy of a JNK Lead Compound IGP in an In Vivo Alzheimer's Disease Model

Project Summary Abstract It is estimated that more than million people in the U S have Alzheimerandapos 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 Imagoandapos 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 IGP 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 IGP in a P S tau transgenic model to determine whether IGP 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 IGP will improve neuronal function and lower A levels and hyperphosphorylation of tau Upon successful completion of these aims we will have demonstrated that IGP is highly effective in reducing the functional and histopathological alterations observed in this AD model This data will allow nomination of IGP 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 Project Narrative Alzheimerandapos 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 Imagoandapos s drug could slow or eliminate AD patientsandapos loss of memory and decline in cognitive abilities