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 (DC 50 = 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.