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

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.