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, <b>7a</b>,<b>b</b>, <b>8a</b>,<b>b</b> and <b>9a</b>,<b>b</b>, targeti...
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| Main Authors: | , , , , , |
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| Format: | Book |
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MDPI AG,
2023-05-01T00:00:00Z.
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| Summary: | The search for disease-modifying agents targeted against Parkinson's disease led us to rationally design a small array of six Anle138b-centered PROTACs, <b>7a</b>,<b>b</b>, <b>8a</b>,<b>b</b> and <b>9a</b>,<b>b</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, <b>8a</b>,<b>b</b> and <b>9a</b>,<b>b,</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 <b>8a</b> was characterized as the most promising αSyn aggregation inhibitor/degradation inducer, with potential usefulness against synucleinopathies and cancer. |
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| Item Description: | 10.3390/pharmaceutics15051467 1999-4923 |