Dihydroquinazolines enhance 20S proteasome activity and induce degradation of α-synuclein, an intrinsically disordered protein associated with neurodegeneration.

Autor: Fiolek TJ; Department of Chemistry, Michigan State University, East Lansing, MI 48824, United States., Magyar CL; Department of Chemistry, Lake Superior State University, Sault Sainte Marie, MI 49783, United States., Wall TJ; Department of Chemistry, Lake Superior State University, Sault Sainte Marie, MI 49783, United States., Davies SB; Department of Chemistry, Lake Superior State University, Sault Sainte Marie, MI 49783, United States., Campbell MV; Department of Chemistry, Lake Superior State University, Sault Sainte Marie, MI 49783, United States., Savich CJ; Department of Chemistry, Lake Superior State University, Sault Sainte Marie, MI 49783, United States., Tepe JJ; Department of Chemistry, Michigan State University, East Lansing, MI 48824, United States. Electronic address: tepe@chemistry.msu.edu., Mosey RA; Department of Chemistry, Lake Superior State University, Sault Sainte Marie, MI 49783, United States. Electronic address: rmosey@lssu.edu.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2021 Mar 15; Vol. 36, pp. 127821. Date of Electronic Publication: 2021 Jan 27.
DOI: 10.1016/j.bmcl.2021.127821
Abstrakt: Aggregates or oligomeric forms of many intrinsically disordered proteins (IDPs), including α-synuclein, are hallmarks of neurodegenerative diseases, like Parkinson's and Alzheimer's disease, and key contributors to their pathogenesis. Due to their disordered nature and therefore lack of defined drug-binding pockets, IDPs are difficult targets for traditional small molecule drug design and are often referred to as "undruggable". The 20S proteasome is the main protease that targets IDPs for degradation and therefore small molecule 20S proteasome enhancement presents a novel therapeutic strategy by which these undruggable IDPs could be targeted. The concept of 20S activation is still relatively new, with few potent activators having been identified thus far. Herein, we synthesized and evaluated a library of dihydroquinazoline analogues and discovered several promising new 20S proteasome activators. Further testing of top hits revealed that they can enhance 20S mediated degradation of α-synuclein, the IDP associated with Parkinson's disease.
(Copyright © 2021 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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