A β-glucuronidase-responsive albumin-binding prodrug for potential selective kinase inhibitor-based cancer chemotherapy

Eur J Med Chem. 2018 Oct 5:158:1-6. doi: 10.1016/j.ejmech.2018.08.100. Epub 2018 Sep 3.

Abstract

We report on the synthesis and in vitro biological evaluations of a nanomolar protein kinase inhibitor (PKI) and its β-glucuronidase-responsive albumin-binding prodrug. The highly potent PKI is 400-3400 times more cytotoxic than the well-known PKI Roscovitine. The prodrug is able to bind covalently to human serum albumin through Michael addition and release the cytotoxic PKI in the presence of β-glucuronidase, an enzyme over-expressed in the microenvironment of solid tumours.

Keywords: Cancer; Chemotherapy; Drug delivery; Protein kinase inhibitor; Self-immolative linker; Tumour microenvironment; β-Glucuronidase-responsive albumin-binding prodrug.

MeSH terms

  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / metabolism
  • Antineoplastic Agents / pharmacology*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Glucuronidase / metabolism*
  • Humans
  • Models, Molecular
  • Neoplasms / drug therapy
  • Neoplasms / metabolism
  • Prodrugs / chemistry
  • Prodrugs / metabolism
  • Prodrugs / pharmacology*
  • Protein Binding
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / metabolism
  • Protein Kinase Inhibitors / pharmacology*
  • Serum Albumin, Human / metabolism*

Substances

  • Antineoplastic Agents
  • Prodrugs
  • Protein Kinase Inhibitors
  • Glucuronidase
  • Serum Albumin, Human