Traditionally, PROTAC optimization is both time-consuming and costly, often requiring extensive cell-based assays due to the large and complex nature of these degraders. This work outlines how the D2B approach bypasses many of these delays by combining automated chemistry and rapid biological screening in a single high-throughput process, enabling faster and more efficient exploration of potential PROTAC candidates.
This poster showcases the synthesis of an 80-member PROTAC library using a 96-well plate-based system, incorporating a variety of linker designs to optimize ADME/DMPK properties. The direct-to-biology workflow dramatically reduces solvent usage, minimizes purification steps, and shortens reaction times from several weeks to just five days. By automating key steps like amide coupling and QC analysis, the team produced and screened crude compounds directly in a BRD4-HiBiT degradation assay, efficiently identified promising hits.
The results demonstrate how a direct-to-biology approach can rapidly generate PROTAC degraders, making high-throughput synthesis and structure-activity relationship (SAR) optimization viable within days rather than months.
This method provides a scalable, cost-effective alternative to conventional approaches, enabling the rapid development of potent, selective degraders with significant potential in PROTAC discovery and therapeutic applications.
