Mitophagy inhibitors for treatment of Alzheimer's Disease

DESCRIPTION provided by applicant Millions currently suffer from Alzheimerandapos s disease AD as life expectancy increases it will become increasingly widespread AD results from the degeneration and death of neurons of the hippocampus and entorhinal cortex End stage patients require continuous care and AD is currently the sixth leading cause of death in the U S There is currently no cure approved treatments aimed at improving cognition and slowing progression focus primarily on increasing the level of acetylcholine in the brain Such treatments which have serious side effects and relieve AD symptoms only for a limited time cannot prevent neuronal death Thus an urgent need exists to identify novel agents that prevent AD progression by acting on targets that mediate neuronal death The mitochondrion is such a target excess dysfunctional mitochondria in AD linked neurons lower energy efficiency and release reactive oxygen species contributing to neuronal death The dysfunctional mitochondria are cleared by phosphorylation and ubiquitin mediated autophagy mitophagy or degradation in auto phagosomes The ubiquitin pathway component consists of the conjugating enzyme parkin which tags defective mitochondria with ubiquitin for removal and the deubiquitinating enzyme USP which deconjugates ubiquitin preventing the removal of defective mitochondria Normally in AD patients the ability to clear defective mitochondria is overwhelmed and replacement of parkin function by overexpression can rescue AD symptoms in vivo Moreover USP knockout has been shown to enhance parkin activity and increase mitochondrial integrity in neurons These findings lead to the hypothesis that USP is a novel target for developing small molecule inhibitors for treatment of AD USP inhibitors are expected to prevent mitophagy deficiency induced neuronal death thereby hindering progression of AD It is proposed to identify novel modulators of USP by screening a diverse collection of small molecules An enzymatic based USP assay for high throughput screening HTS will be configured and Progenraandapos s compound collection will be screened Confirmed hits will be reordered along with a subset of related analogs and profiled against a series of DUBs and other proteases before initiating a hit to lead optimization program The most promising compounds from this program will be examined in cellular models of mitophagy rescue In phase II the most interesting compounds will be progressed to hit to lead medicinal chemistry optimization with associated DMPK and additional cellular and animal model studies The commercial goal is a novel drug to treat AD PUBLIC HEALTH RELEVANCE Alzheimerandapos s disease AD is devastating in terms of mortality morbidity emotional strain and cost There is currently no cure approved treatments address symptoms but lose efficacy over time and do not prevent neuronal death the root cause of the disease In the proposed project inhibitors of a newly discovered enzyme from the ubiquitin pathway which helps to maintain neuronal cell death will be identified and tested for their ability to stop the progression of symptoms of AD in an animal model Appropriate inhibitors will be developed as novel treatments for AD