Auto-RapTAC: A Versatile and Sustainable Platform for the Automated Rapid Synthesis and Evaluation of PROTAC

The tedious synthesis and limited throughput biological evaluation remain a great challenge for discovering new proteolysis targeting chimera (PROTAC). To rapidly identify potential PROTAC lead compounds, we report a platform named Auto-RapTAC. Based on the modular characteristic of the PROTAC molecule, a streamlined workflow that integrates lab automation with “click chemistry” joint building-block libraries was constructed. This facilitates the autonomous generation of a variety of PROTACs, each with distinct linkers and E3 ligase ligands, all stored in biocompatible solutions. The ready-for-screening (R4S) approach, when paired with fluorescence-based assays, enables the efficient assessment of the PROTAC degradation activity in a high-throughput manner. To further test the capability of the platform, we identify six new PROTACs that target CDK2, CDK12, and BCL6 within a mere 8-day time frame for each target. In all, this platform could find broad application not only in discovering new PROTACs but also in the rapid development of novel heterobifunctional modalities.