Abstract: In PROTAC projects, precise linker length and exit vector geometry are integral for ternary complex formation and efficient degradation. Due to very challenging computational modelling of ternary complexes, exploration of structure-activity-relationship (SAR) is mostly empirical, which requires significant time and resource investment. We have developed a rapid, nanomole scale PROTAC synthesis methodology that allows direct screening of reaction mixtures using cellular degradation assays and logD and ePSA measurements. The approach greatly accelerates (week instead of months) and expands PROTAC SAR exploration by using nanomole amounts of reagent and avoids laborious and solvent-demanding purification. Crude screening does not compromise the quality of the data, which is suitable for identification of actives and prioritization for the synthesis on scale.
M. P. Plesniak, Emilia K. Taylor, Frederik Eisele et.al, “Rapid PROTAC discovery platform: nanomole scale array synthesis and direct screening of reaction mixtures to facilitate the expedited discovery and follow-up of PROTAC hits.” ChemRxiv https://doi.org/10.26434/chemrxiv-2023-dz9l7