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.