A key design feature was the inclusion of a basic centre in the linkers, allowing us to perform a platebased SCX step prior to compound testing to remove any unreacted ligand reagents and related byproducts, which had been observed as a challenge in previous studies 6 . This led to almost all attempted PROTACs being detected via LCMS and the vast majority of failures came from either use of an alpha bromoacetamide electrophile or linkers containing spirocyclic motifs. This highlights both the generally robust nature of the protocol and opportunities for further optimisation. Next, we tested our library in a GSK3β-HiBiT knock-in HEK293 cell line, generating full dose-response curves on all compounds. Once all building blocks and a suitable screening assay were available, we were able to complete the full synthesis and screening workflow in 5 days. This rapidly led us from a position of no-prior in-house GSK3 related degrader data to identifying a large number of hits, with focus falling on 6 molecules that were resynthesised and purified for further profiling. Of particular note, we identified two molecules, KH1 (24) and KH2 (26) that showed DC50 values in the picomolar to single digit nanomolar range and exquisite specificity for degrading both GSK3 paralogs with no other significantly degraded proteins identified. To support the utility of these probes in understanding GSK3 related pathway biology, we investigated their impact on established GSK3 substrates βcatenin and phospho-CRMP2 . Initial data suggests the AD related phospho-CRMP2 is reduced in line with GSK3 degradation. Finally, we discovered that KH1 (24), following a single 5mg/kg i.v. dose was able, within 4 hours, to almost completely remove GSK3β from the liver with partial degradation also observed in mouse brain. Our data support that this is achieved via a combination of moderate brain penetration and potent and rapid degradation kinetics. This study shows that the inherent pharmacokinetic/pharmacodynamic disconnect of PROTACs can be leveraged to avoid the requirement for high and prolonged CNS exposure, which would be required for inhibitors, to achieve on-target modulation in the brain. Whilst an opportunity for some, this may also act as an important warning to those who require avoiding on-target activity in the brain. We hope that the orthogonally reactive linker synthesis and screening approach exemplified here can provide a generalisable strategy to accelerate bifunctional probe discovery and therapeutic concept generation and a benchmark for CNS PROTAC discovery.