SNIPERs—Hijacking IAP activity to induce protein degradation

Abstract

The induction of protein degradation by chimeric small molecules represented by proteolysis-targeting chimeras (PROTACs) is an emerging approach for novel drug development. We have developed a series of chimeric molecules termed specific and non-genetic inhibitor of apoptosis protein (IAP)-dependent protein erasers (SNIPERs) that recruit IAP ubiquitin ligases to effect targeted degradation. Unlike the chimeric molecules that recruit von Hippel–Lindau and cereblon ubiquitin ligases, SNIPERs induce simultaneous degradation of IAPs such as cIAP1 and XIAP along with the target proteins. Because cancer cells often overexpress IAPs—a mechanism involved in the resistance to cancer therapy—SNIPERs could be used to kill cancer cells efficiently.