FIGURE 3.

Design, proposed model, and testing of VHL-targeting tau degraders. (A) Hypothesis model for hetero-bifunctional tau degraders designed to simultaneously bind pathological misfolded tau and the substrate recognition component VHL within the CRL2^VHL E3-ubiquitin ligase complex, to promote tau ubiquitination and proteasomal degradation. (B–D) The VHL series incorporates the T807 core scaffold for tau recognition (B), the VHL ligand VL269 (C) and a variable linker length and composition (D). (E) Summary of chemical properties for VHL-recruiting degrader molecules. (F–L) Concentration effect of VHL degraders on total tau (TAU5) and P-tau S396 levels in A152T neurons (6-week differentiated) after 24 h of treatment, measured by ELISA. Data points represent mean tau levels (μg of tau normalized to total protein in the lysate) relative to vehicle samples ± SEM (n = 3). The 0 μM degrader data points correspond to vehicle alone (DMSO) control treatment. Statistics: 2-tailed unpaired Student’s t-test for each concentration relative to vehicle; ^nsP > 0.05, *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.