Early evaluation of opportunities in oral delivery of PROTACs to overcome their molecular challenges

Drug Discov Today. 2024 Feb;29(2):103865. doi: 10.1016/j.drudis.2023.103865. Epub 2023 Dec 26.

Abstract

PROteolysis TArgeting Chimeras (PROTACs) offer new opportunities in modern medicine by targeting proteins that are intractable to classic inhibitors. Heterobifunctional in nature, PROTACs are small molecules that offer a unique mechanism of protein degradation by hijacking the ubiquitin-mediated protein degradation pathway, known as the ubiquitin-proteasome system. Herein, we present an analysis on the structural characteristics of this novel chemical modality. Furthermore, we review and discuss the formulation opportunities to overcome the oral delivery challenges of PROTACs in drug discovery.

Keywords: PROTAC; amorphous solid dispersions (ASDs); drug delivery; drug discovery; lipid-based formulations (LBF).

Publication types

  • Review

MeSH terms

  • Proteasome Endopeptidase Complex / metabolism
  • Proteins / metabolism
  • Proteolysis
  • Proteolysis Targeting Chimera*
  • Ubiquitin-Protein Ligases* / metabolism
  • Ubiquitins / metabolism

Substances

  • Ubiquitin-Protein Ligases
  • Proteolysis Targeting Chimera
  • Proteasome Endopeptidase Complex
  • Proteins
  • Ubiquitins