A platform for the rapid synthesis of proteolysis targeting chimeras (Rapid-TAC) under miniaturized conditions

Proteolysis targeting chimera (PROTAC) is one of the most frequently used technologies for targeted protein degradation. PROTACs are composed of target protein ligand, E3 ligase ligand and a linker between them. Traditional methods for the development of PROTACs involve step-by-step synthesis and are time consuming. Herein, we report a platform for the rapid synthesis of PROTACs (Rapid-TAC) via a traceless coupling reaction between ortho-phthalaldehyde (OPA) motif on the ligand of targeting protein and an amine fucntional group on the commercially available partial PROTAC library that is composed of different E3 ligase ligands and various types and lengths of linkers. Under our optimized miniaturized conditions, the full PROTACs can be synthesized in a high throughput manner and the products can be directly used for screening without any further manipulations including purification. We demonstrated the utility of this platform by quickly identifying active degraders for androgen receptor (AR) and BRD4 with DC₅₀ of 41.9 nM and 8.9 nM, respectively. It is expected that this Rapid-TAC platform can be easily extended to many other targets, thus lowering the barrier to access this novel modelity for small molecule drug discovery and faciliate structure activity relationship studies.