Small molecule Parkin activators to treat Alzheimer's Disease

Alzheimer s diseaseADaffects an estimatedmillion worldwidethis number will double in the next decadeAD results from the degeneration and death of hippocampal and entorhinal cortex neurons in the brainwhich are critical for learning and memoryPatients in end stage AD require round the clock careUltimately fatal with no cure availableAD is the sixth leading cause of death in the USCurrent therapies have serious side effects and cannot prevent neuronal death and disease progressionleading to efforts to identify novel therapeutics that stop AD progressionOne target for such therapy is the mitochondrionMitochondrial damage and the appearance of autophagic vacuoles correlate with AD onsetand evidence suggests that mitophagya regulatory form of autophagic degradation mediated by the ubiquitin Eligase Parkin and the kinase PINKis overwhelmed and cannot prevent accumulation of damaged mitochondria in AD affected neuronsDysfunctional mitochondria in the axons of AD linked neurons diminish energy production and release harmful reactive oxygen speciesin these neuronsdysfunctional mitochondria accumulate due to inadequate mitophagyThustherapeutic intervention in this compromised Parkin and PINKmediated mitophagy pathway is a promising strategy to improve mitochondrial integritypreventing AD progressionSupporting this notionoverexpression of Parkin in an AD mouse model ameliorates AD related symptomswith improved mitochondrial integrityNotablythe key factor of the mitophagy pathwayParkinis known to exist in an auto inhibitedoffstate in cytosolwith very low basal level enzymatic activityIts auto inhibition is mediated by multiple intramolecular interactionsand point mutations that specifically disrupt these interactions activate Parkin activity and promote its translocation to dysfunctional mitochondriaThe therapeutic hypothesis driving the current application is that small molecules that relieve auto inhibitory interactions within Parkin can be used to selectively activate Parkin activity and facilitate mitochondrial healthParkin activators are expected to prevent neuronal death induced by defective mitophagythereby hindering the progression of ADIt is proposed in this Phase II application to initiate preclinical development of selected small molecule activators of Parkinidentified in Phase I and shown to relieve auto inhibition of Parkinaugmenting mitophagy in cellsThis will be accomplished by performing lead optimization of selected Parkin activatorsperforming ADME DMPK analysesin vitro and in vivoon compounds of interestand demonstrating efficacy of optimized compounds in cellular and animal models of AD related neurodegenerationThe ultimate commercial goal is the development of a novel small molecule agonist that can be used to treat neurological diseases with mitochondrial dysfunction