Nanoformulation of BRD4-Degrading PROTAC: Improving Druggability To Target the 'Undruggable' MYC in Pancreatic Cancer

Trends Pharmacol Sci. 2020 Oct;41(10):684-686. doi: 10.1016/j.tips.2020.08.008. Epub 2020 Sep 4.

Abstract

In a recent study, Saraswat and colleagues identified a novel proteolysis targeting chimera (PROTAC), ARV-825 (ARV), that efficiently degrades bromodomain-containing protein 4 (BRD4) to drug the 'undruggable' MYC in pancreatic cancer. ARV-loaded polyethylene glycol-poly lactic acid-co-glycolic acid (PLGA-PEG) polymeric nanoparticles (ARV-NPs) showed promising anticancer activity in both 2D cell culture and 3D multicellular tumor spheroid models of pancreatic cancer. This study demonstrates a unique therapeutic strategy in which targeting BRD4 for degradation via the E3 ubiquitin ligase cereblon (CRBN) pathway leads to sustained inhibition of oncogenic MYC expression for effective treatment of pancreatic cancer.

Keywords: ARV-825; BRD4; MYC; PROTAC; pancreatic cancer; polymeric nanoparticles.

Publication types

  • Research Support, N.I.H., Extramural
  • Comment

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Cell Cycle Proteins / metabolism
  • Cell Line, Tumor
  • Humans
  • Nuclear Proteins* / metabolism
  • Pancreatic Neoplasms* / drug therapy
  • Peptide Hydrolases
  • Proteolysis
  • Transcription Factors / metabolism
  • Ubiquitin-Protein Ligases

Substances

  • Adaptor Proteins, Signal Transducing
  • BRD4 protein, human
  • Cell Cycle Proteins
  • CRBN protein, human
  • Nuclear Proteins
  • Peptide Hydrolases
  • Transcription Factors
  • Ubiquitin-Protein Ligases