Solid-phase approaches could offer many advantages over conventional PROTAC synthesis if the same chemistries and topographic diversity can be incorporated. We have examined solid-phase synthesis of both VHL-targeting PROTACS and IAP-targeting SNIPERS using backbone-amide linked (BAL resin) completing 8–11 step syntheses with products obtained with a single purification step.

Abstract

Developing straightforward but flexible approaches to PROTAC synthesis that can incorporate the structural elements of emerging designs can improve the quality and efficiency of PROTAC development. Solid-phase approaches could offer many advantages over conventional PROTAC synthesis if diverse chemistries and topographies can be incorporated. We have exploited the backbone-amide-linked (BAL) resin to employ an array of solid-phase organic reactions, providing access to VHL- and IAP-targeting degraders using the BRD4-targeting JQ1 conjugates as examples.