Design, synthesis and biological evaluation of the tumor hypoxia-activated PROTACs bearing caged CRBN E3 ligase ligands

Bioorg Med Chem. 2023 Mar 15:82:117237. doi: 10.1016/j.bmc.2023.117237. Epub 2023 Mar 8.

Abstract

Tumor hypoxia-activated proteolysis targeting chimeras (ha-PROTACs) 9 and 10 were designed and synthesized by incorporating the hypoxia-activated leaving group (1-methyl-2-nitro-1H-imidazol-5-yl)methyl or 4‑nitrobenzyl into the structure of the cereblon (CRBN) E3 ligand of an epidermal growth factor receptor 19 deletions (EGFRDel19-based PROTAC 8. The in vitro protein degradation assay demonstrated that 9 and 10 could effectively and selectively degrade EGFRDel19 in tumor hypoxia. Meanwhile, these two compounds showed higher potency in inhibiting cell viability and migration, as well as in promoting cells apoptosis in tumor hypoxia. Moreover, nitroreductase reductive activation assay indicated that prodrugs 9 and 10 could successfully release the active compound 8. This study confirmed the feasibility to develop ha-PROTACs to enhance the selectivity of PROTACs by caging CRBN E3 ligase ligand.

Keywords: Anticancer; CRBN E3 ligase ligand; EGFR; Hypoxia; PROTAC.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Ligands
  • Proteolysis
  • Proteolysis Targeting Chimera*
  • Tumor Hypoxia
  • Ubiquitin-Protein Ligases* / metabolism

Substances

  • Ubiquitin-Protein Ligases
  • Ligands
  • Proteolysis Targeting Chimera