alphaSyn PROTAC 2b

alphaSyn PROTAC 2b is a CRBN dependent degrader of alpha-synuclein (aSyn) with single digit micromolar potency and adequate selectivity in both in vitro (HEK293T and SH-SY5Y seeded with aSyn fibrils) and in vivo (C. elegans) models of synucleinopathies. Mechanistic experiments indicate the engagement of the ubiquitin proteasome system as well as the autophagy-lysosome pathway in mediating clearance of the aSyn aggregates. In addition to aSyn, 10 other proteins were identified by global proteomics as differentially expressed upon 10 uM treatment aSyn PROTAC 2b; more data is needed to establish the relationships between PROTAC 2b, those proteins, and the observed clearance of aSyn aggregates. An N-methylated analog of 2b acts a convenient negative control in experiments. Moreover, as selectivity data from a global proteomics profile is not available at 20 uM, (only up to 10 uM) there could be unknown off-targets effects at 20 uM, but 20 uM is the highest concentration tested before the hook effect at 40 uM (figure 3b).

The Probe is a good tool to examinate facts about alphaSyn aggregates and their degradation. The DC50 and Kd values are relatively high, suggesting weaker binding affinity. However, Figure 3 indicates a lower DC50 than stated. Additionally, the proof of target engagement is incomplete, though the negative control gives a good indication on target engagement. The Hook effect has to be established. Note: Typos are present in Figure 3d of the cited publication where the concentration should be shown as time frame of treatment (h).