Design, Synthesis, and Biological Evaluation of Potent 20S Proteasome Activators for the Potential Treatment of α‑Synucleinopathies

While neurodegenerative diseases
affect millions of patients worldwide,
there are insufficient available therapeutics to halt or slow down
the progression of these diseases. A key pathological feature of several
neurodegenerative diseases is the oligomerization and aggregation
of specific intrinsically disordered proteins (IDPs) creating neuronal
deposits, such as Lewy bodies in Parkinson’s disease. Clearance
of these pathogenic, aggregation-prone IDPs is mediated by the 20S
isoform of the human proteasome. Thus, enhancing the 20S proteasome-mediated
proteolysis could be a very useful therapeutic pathway to prevent
neurotoxicity. Here, we report the successful development of sub-microM
20S proteasome activators based on a phenothiazine scaffold. This
class of compounds prevented the accumulation of pathologically relevant
IDPs, such as the pathogenic A53T mutated α-synuclein, in vitro and in mammalian cell lines.