Small molecule Parkin activators to treat Alzheimer's Disease

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Alzheimer’s disease (AD) affects an estimated 21-35 million worldwide; this number will double in the next decade. AD results from the degeneration and death of hippocampal and entorhinal cortex neurons in the brain, which are critical for learning and memory. Patients in end stage AD require round-the-clock care. Ultimately fatal with no cure available, AD is the sixth-leading cause of death in the US. Current therapies have serious side effects and cannot prevent neuronal death and disease progression, leading to efforts to identify novel therapeutics that stop AD progression. One target for such therapy is the mitochondrion. Mitochondrial damage and the appearance of autophagic vacuoles correlate with AD onset, and evidence suggests that mitophagy, a regulatory form of autophagic degradation mediated by the ubiquitin E3 ligase Parkin and the kinase PINK1, is overwhelmed and cannot prevent accumulation of damaged mitochondria in AD-affected neurons. Dysfunctional mitochondria in the axons of AD-linked neurons diminish energy production and release harmful reactive oxygen species; in these neurons, dysfunctional mitochondria accumulate due to inadequate mitophagy. Thus, therapeutic intervention in this compromised Parkin and PINK1-mediated mitophagy pathway is a promising strategy to improve mitochondrial integrity, preventing AD progression. Supporting this notion, overexpression of Parkin in an AD mouse model ameliorates AD-related symptoms, with improved mitochondrial integrity. Notably, the key factor of the mitophagy pathway, Parkin, is known to exist in an auto-inhibited ‘off’ state in cytosol, with very low basal level enzymatic activity. Its auto-inhibition is mediated by multiple intramolecular interactions, and point mutations that specifically disrupt these interactions activate Parkin activity and promote its translocation to dysfunctional mitochondria. The 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 health. Parkin activators are expected to prevent neuronal death induced by defective mitophagy, thereby hindering the progression of AD. It is proposed in this Phase II application to initiate preclinical development of selected small molecule activators of Parkin, identified in Phase I and shown to relieve auto-inhibition of Parkin, augmenting mitophagy in cells. This will be accomplished by performing lead optimization of selected Parkin activators, performing ADME/DMPK analyses (in vitro and in vivo) on compounds of interest, and demonstrating efficacy of optimized compounds in cellular and animal models of AD-related neurodegeneration. The ultimate commercial goal is the development of a novel small molecule agonist that can be used to treat neurological diseases with mitochondrial dysfunction.