Design, Synthesis, and Biological Evaluation of Substituted Hydroxyquinolinone Compounds as 20S Proteasome Enhancers

Abstract ID 128480 Poster Board 093 The 20S proteasome is a key component in cellular proteostasis and assists the cell in maintaining proper levels of intrinsically disordered proteins (IDPs). Dysregulation of 20S proteasome-mediated proteolytic degradation often results in the accumulation and aggregation of these IDPs, which are involved in the pathogenesis of neurodegenerative diseases, such as Parkinson's disease. Here, it is hypothesized that using small molecules to enhance the 20S proteasome's degradation of IDPs may prove a viable strategy to combat this toxic protein accumulation. A hydroxyquinolinone compound (MSU-8) was recently identified as a potential lead, and this work focuses on expanding its structure-activity relationship (SAR). We gratefully acknowledge the National Institute of Aging (R61/33 NS111347) for their financial support.