An Integrated Direct-to-Biology Platform for the Nanoscale Synthesis and Biological Evaluation of PROTACs

• DOI: 10.26434/chemrxiv-2023-1b47d-v2
• Publication Date: 2023-09-01T08:04:18Z
• Authors: Rebecca Stevens; Enrique Bendito-Moll; David Battersby; Afjal Miah; Natalie Wellaway; Robert Law; Peter Stacey; Diana Klimaszewska; Justyna Macina; Glenn Burley; John Harling
• Keywords: Synthetic Biology

ABSTRACT: Proteolysis targeting chimeras (PROTACs) are heterobifunctional molecules that co opt the cell’s natural proteasomal degradation mechanisms to selectively tag and degrade undesired proteins. However, a challenge associated with PROTACs is difficult optimisation required identify new degraders, thus development of high-throughput platforms for their synthesis biological evaluation required. In this study, we establish an ultra experimentation (ultraHTE) platform PROTAC synthesis, followed by direct addition crude reaction mixtures cellular assays without any purification. This ‘Direct-to-Biology’ (D2B) approach was validated, then exem-plified in medicinal chemistry campaign novel BRD4 from BRD4-binding scaffold previously unexplored targeted protein degradation. Using D2B platform, over 600 carried out 1536-well plate subsequent these candidates performed single scientist less than one month, set picomolar degraders. Due its ability hugely accelerate anticipate our transform testing PROTACs.