Discovery of Small-Molecule Degraders for Alpha-Synuclein Aggregates

Alpha-synuclein (αSyn) species, especially the
oligomers
and fibers, are associated with multiple neurodegenerative diseases
and cannot be directly targeted under the conventional pharmacological
paradigm. Proteolysis-targeting chimera technology confers degradation
of various “undruggable” targets; however, hardly any
small-molecule degrader for αSyn aggregates has been reported
yet. Herein, by using the probe molecule sery308 as a warhead, a series
of small-molecule degraders for αSyn aggregates were designed
and synthesized. Their degradation effects on αSyn aggregates
were evaluated on a modified pre-formed fibril-seeding cell model.
Compound 2b exhibited the highest degradation efficiency
(DC50 = 7.51 ± 0.53 μM) with high selectivity.
Mechanistic exploration revealed that both proteasomal and lysosomal
pathways were involved in this kind of degradation. Moreover, the
therapeutic effects of 2b were tested on SH-SY5Y (human
neuroblastoma cell line) cells and Caenorhabditis elegans. Our results provided a new class of small-molecule candidates against
synucleinopathies and broadened the substrate spectrum of PROTAC-based
degraders.