Synthesis and Preliminary Characterization of Putative Anle138b-Centered PROTACs against α-Synuclein Aggregation.

The search for disease-modifying agents targeted against Parkinson's disease led us to rationally design a small array of six Anle138b-centered PROTACs, 7a , b , 8a , b and 9a , b , targeting αSynuclein (αSyn) aggregates for binding, polyubiquitination by the E3 ligase Cereblon (CRBN), and proteasomal degradation. Lenalidomide and thalidomide were used as CRBN ligands and coupled with amino- and azido Anle138b derivatives through flexible linkers and coupling reactions (amidation, 'click' chemistry). Four Anle138b-PROTACs, 8a , b and 9a , b, were characterized against in vitro αSyn aggregation, monitoring them in a Thioflavin T (ThT) fluorescence assay and in dopaminergic neurons derived from a set of isogenic pluripotent stem cell (iPSC) lines with SNCA multiplications. Native and seeded αSyn aggregation was determined with a new biosensor, and a partial correlation between αSyn aggregation, cellular dysfunctions, and neuronal survival was obtained. Anle138b-PROTAC 8a was characterized as the most promising αSyn aggregation inhibitor/degradation inducer, with potential usefulness against synucleinopathies and cancer.