Discovery of Effective Dual PROTAC Degraders for Neurodegenerative Disease-Associated Aggregates

J Med Chem. 2024 Mar 14;67(5):3448-3466. doi: 10.1021/acs.jmedchem.3c01719. Epub 2024 Feb 14.

Abstract

The aggregation of specific proteins is a histopathological hallmark in various neurodegenerative diseases (NDs), among which Alpha-synuclein (α-Syn) and tau have received increased attention. The targeted protein degradation (TPD) strategy has been studied in the treatment of NDs, but multitarget bifunctional molecules have been ignored. Herein, a series of effective dual PROTAC degraders were developed, which could degrade α-Syn aggregates and total tau simultaneously. The degradation effects were evaluated in vitro, and the results showed that T3 could significantly knockdown α-Syn aggregates and total tau in the degradation efficiency with DC50 of 1.57 ± 0.55 and 4.09 ± 0.90 μM, respectively. Further mechanistic exploration showed that the degradation effect was mediated by the ubiquitin-proteasome system (UPS). Additionally, the therapeutic efficacy of T3 was confirmed in an MPTP-induced PD mouse model. Our results suggest that these dual PROTACs may provide a potential therapeutic strategy for NDs.

MeSH terms

  • Animals
  • Disease Models, Animal
  • Mice
  • Neurodegenerative Diseases* / drug therapy
  • Proteasome Endopeptidase Complex / metabolism
  • Proteolysis
  • Ubiquitin / metabolism

Substances

  • Proteasome Endopeptidase Complex
  • Ubiquitin