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 DC 50 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.

Drug Development for Alzheimer’s and Parkinson’s Disease: Where Do We Go Now?

“…Targeted protein degradation (TDP) technologies include proteolysis-targeting chimeras (PROTACs), autophagy-targeting chimeras (AUTACs), and autophagosome-anchoring chimeras (ATACCs). Although the application of TDP technologies for NDs is still in its infancy, recent studies have shown that their use is a strategy worth exploring [ 299 , 300 ]. The combination of TDP technologies with multitarget strategies is also a direction that can be followed.…”

Targeted protein degradation in CNS disorders: a promising route to novel therapeutics?

“…Therapeutic development for CNS diseases is challenging due to blood brain barrier (BBB) permeability constraints, and in the druggability of protein aggregates which often characterize neurodegenerative pathologies. Commonly used degrader approaches have the potential to target proteins or aggregated complexes for degradation by the ubiquitin-proteasome (UPS) system ( Bekes et al, 2022 ; Zhu et al, 2024 ) or autophagy-lysosome machinery ( Pei et al, 2021 ; Ji et al, 2022 ). Targeted protein degraders act through event-driven pharmacology via non-reversible removal of functional components, and their potency is boosted by a catalytic mode of action (MOA), enabling sub-stoichiometric dosing regimens ( Bekes et al, 2022 ).…”