SNIPERs-Hijacking IAP activity to induce protein degradation

Drug Discov Today Technol. 2019 Apr;31:35-42. doi: 10.1016/j.ddtec.2018.12.002. Epub 2019 Jan 14.

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.

Publication types

  • Review

MeSH terms

  • Animals
  • Humans
  • Inhibitor of Apoptosis Proteins / metabolism*
  • Leucine / analogs & derivatives
  • Leucine / pharmacology
  • Neoplasms / metabolism
  • Proteolysis*

Substances

  • (-)-N-((2S,3R)-3-amino-2-hydroxy-4-phenyl-butyryl)-L-leucine methyl ester
  • Inhibitor of Apoptosis Proteins
  • Leucine