Small Molecule Epichaperome Inhibitors for the Treatment of Neurodegenerative Diseases (PU-AD) and Cancers (PU-H71)

The hallmark of neurodegenerative diseases is the breakdown of regulatory pathways designed to prevent aggregation and accumulation of disease associated aberrant proteins. Protein degradation systems such as the ubiquitin-mediated proteasome or autophagy are overburdened or decreased failing to effectively degrade and clear aberrant proteins.

In this cellular stress environment epichaperomes form to stabilize aberrant proteins thus contributing to the pathophysiology of diseases such as Alzheimer’s, Parkinson’s and ALS. Selective inhibition of epichaperomes with PU-AD not only prevents stabilization and aggregation of aberrant proteins but also initiates and enhances their degradation which results in neuronal survival with no effect on normal cells.

In cancer, epichaperomes confer functionality to proteins driving proliferation of cancer cells by facilitating their folding and activation. In contrast to neuronal diseases, in cancer inhibition of epichaperomes by PU-H71 results in the degradation of proteins that drive the cancer pathology and in cell death without affecting normal cells.