β-Glucuronidase triggers extracellular MMAE release from an integrin-targeted conjugate

Org Biomol Chem. 2019 May 15;17(19):4705-4710. doi: 10.1039/c9ob00617f.

Abstract

A non-internalizing αvβ3 integrin ligand was conjugated to the anticancer drug MMAE through a β-glucuronidase-responsive linker. In the presence of β-glucuronidase, only the conjugate bearing a PEG4 spacer inhibited the proliferation of integrin-expressing cancer cells at low nanomolar concentrations, indicating important structural requirements for the efficacy of these therapeutics.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Dose-Response Relationship, Drug
  • Drug Screening Assays, Antitumor
  • Glioblastoma / drug therapy*
  • Glioblastoma / metabolism
  • Glioblastoma / pathology
  • Glucuronidase
  • Humans
  • Integrin alphaVbeta3 / antagonists & inhibitors*
  • Integrin alphaVbeta3 / chemistry
  • Integrin alphaVbeta3 / metabolism
  • Ligands
  • Molecular Conformation
  • Oligopeptides / chemical synthesis
  • Oligopeptides / chemistry
  • Oligopeptides / pharmacology*
  • Structure-Activity Relationship
  • Vitronectin / antagonists & inhibitors
  • Vitronectin / chemistry
  • Vitronectin / metabolism

Substances

  • Antineoplastic Agents
  • Integrin alphaVbeta3
  • Ligands
  • Oligopeptides
  • Vitronectin
  • Glucuronidase
  • monomethyl auristatin E