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

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:36

Article

Fiolek, Taylor J.¹  Magyar, Christina L.²  Wall, Tyler J.²  Davies, Steven B.²  Campbell, Molly, V²  Savich, Christopher J.²  Tepe, Jetze J.¹  Mosey, R. Adam² 

[1] Michigan State Univ, Dept Chem, E Lansing, MI 48824 USA

[2] Lake Super State Univ, Dept Chem, Sault Sainte Marie, MI 49783 USA

关键词: Proteasome;    Activation;    Neurodegenerative diseases;    Parkinson’ s disease;    Undruggable;   

DOI  :  10.1016/j.bmcl.2021.127821

来源: Elsevier

【 摘 要 】

Aggregates or oligomeric forms of many intrinsically disordered proteins (IDPs), including alpha-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 alpha-synuclein, the IDP associated with Parkinson's disease.

【 授权许可】

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