Emerging degrader technologies engaging lysosomal pathways

Chem Soc Rev. 2022 Oct 31;51(21):8832-8876. doi: 10.1039/d2cs00624c.

Abstract

Targeted protein degradation (TPD) provides unprecedented opportunities for drug discovery. While the proteolysis-targeting chimera (PROTAC) technology has already entered clinical trials and changed the landscape of small-molecule drugs, new degrader technologies harnessing alternative degradation machineries, especially lysosomal pathways, have emerged and broadened the spectrum of degradable targets. We have recently proposed the concept of autophagy-tethering compounds (ATTECs) that hijack the autophagy protein microtubule-associated protein 1A/1B light chain 3 (LC3) for targeted degradation. Other groups also reported degrader technologies engaging lysosomal pathways through different mechanisms including AUTACs, AUTOTACs, LYTACs and MoDE-As. In this review, we analyse and discuss ATTECs along with other lysosomal-relevant degrader technologies. Finally, we will briefly summarize the current status of these degrader technologies and envision possible future studies.

Publication types

  • Review

MeSH terms

  • Autophagy
  • Drug Discovery*
  • Lysosomes / metabolism
  • Proteins* / metabolism
  • Proteolysis

Substances

  • Proteins