Proteolysis targeting chimeras (PROTACs) are small molecules that hijack the ubiquitin proteosome system in order to label proteins of interest (POI) for degradation. PROTACs are comprised of a POI binder and an E3 ligase recruiting element (E3RE) that are covalently tethered by a linker. Recent studies have highlighted the importance of the linker’s role to afford stable and long-lived ternary complexes. Long-lived complexes appear to be necessary for efficient ubiquitination and degradation.1, 2 Therefore, efficient strategies are required to identify optimal linkers that generate a stable ternary complex. To address this, we have designed diverse library of linkers utilising Tanimoto similarity and pharmacophore diversity metrics, whilst simultaneously enriching for linkers that are found in active PROTACs.3 From this analysis we selected a 43-membered linker library. The library was used to synthesise potential PROTACs in parallel and at microscale (2.5 µmol).4 The products from this parallel synthesis have been screened as crude reaction mixtures using surface plasmon resonance (SPR). We hypothesise that this will enable long lived ternary complexes to be identified via “off-rate screening”.5 In this work, I will present our preliminary data on the utility of this approach against two POIs.