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

Abstract

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.

Perspective Strategies for Interventions in Parkinsonism: Remedying the Neglected Role of TPPP

“…Some SYN-specific PROTAC constructs are also available [80][81][82][83][84]. These PROTAC molecules target SYN either directly or indirectly (Table 2).…”

Navigating α‐Synuclein Aggregation Inhibition: Methods, Mechanisms, and Molecular Targets

“…It is a conjugate of anle138b with UBQ E3 ligase ligand that was expected to attract ubiquitin ligase close to amyloid fibrils and accelerate their ubiquitination and further degradation by cellular machinery. [132] The same approach was applied also to the analogous compound sery308 [133] (Figure 5A).…”