Development of hypoxia-activated PROTAC exerting a more potent effect in tumor hypoxia than in normoxia

Chem Commun (Camb). 2021 Nov 30;57(95):12852-12855. doi: 10.1039/d1cc05715d.

Abstract

Hypoxia is a hallmark of many solid tumors, and it causes the overexpression of a variety of proteins including the epidermal growth factor receptor (EGFR). Many antitumor prodrugs have been designed to target hypoxia. Here we report the identification of a kind of hypoxia-activated proteolysis targeting chimera (ha-PROTAC) by introducing the hypoxia-activated leaving group (1-methyl-2-nitro-1H-imidazol-5-yl)methyl or 4-nitrobenzyl into the structure of an EGFRDel19-based PROTAC. Among the obtained molecules, ha-PROTAC 13 exhibits a more potent degradation activity for EGFRDel19 in hypoxia than in normoxia in HCC4006 cells. This is the first example of identifying a PROTAC to selectively act on tumors utilizing the characteristic of tumor hypoxia and provides a new approach for PROTAC development.

MeSH terms

  • Drug Development*
  • ErbB Receptors / antagonists & inhibitors
  • ErbB Receptors / metabolism
  • Humans
  • Imidazoles / chemical synthesis
  • Imidazoles / chemistry
  • Imidazoles / pharmacology*
  • Molecular Structure
  • Nitrobenzenes / chemical synthesis
  • Nitrobenzenes / chemistry
  • Nitrobenzenes / pharmacology*
  • Proteolysis / drug effects
  • Tumor Hypoxia / drug effects*

Substances

  • Imidazoles
  • Nitrobenzenes
  • EGFR protein, human
  • ErbB Receptors