1. Academic Validation
  2. Design, Synthesis, and Biological Evaluation of Potent 20S Proteasome Activators for the Potential Treatment of α-Synucleinopathies

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

  • J Med Chem. 2022 May 12;65(9):6631-6642. doi: 10.1021/acs.jmedchem.1c02158.
Sophia D Staerz 1 Corey L Jones 1 Jetze J Tepe 1
Affiliations

Affiliation

  • 1 Department of Chemistry, Michigan State University, East Lansing, Michigan 48823, United States.
Abstract

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.

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