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

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.