Traceless Staudinger ligation enabled parallel synthesis of proteolysis targeting chimera linker variants

A parallel, one-pot assembly approach to proteolysis targeting chimeras (PROTACs) is demonstrated utilizing activated esters generated in situ, and traceless Staudinger ligation chemistry. The method described allows for rapid structure-activity relationship studies of PROTAC linker variants. Two previously studied systems, cereblon and BRD4 degraders, are examined as test cases for the synthetic method. The two related strategies to assemble PROTAC linker variants discussed can accommodate the chromotographic separations capabilities of labs of many sizes and incorporates commercially available degrader building blocks, thereby easing synthetic entry into PROTAC chemical space.

Automated summary

This article demonstrates a rapid assembly approach for PROTAC variants using activated esters and Staudinger ligation. By testing previously studied systems, the feasibility of the synthetic method is verified, and two strategies for assembling PROTAC linker variants are discussed.