Zap-Pano: a Photocaged Prodrug of the KDAC Inhibitor Panobinostat

ChemMedChem. 2021 Dec 14;16(24):3691-3700. doi: 10.1002/cmdc.202100403. Epub 2021 Jul 29.

Abstract

We report the synthesis and biological evaluation of a light-activated (caged) prodrug of the KDAC inhibitor panobinostat (Zap-Pano). We demonstrate that addition of the 4,5-dimethoxy-2-nitrobenzyl group to the hydroxamic acid oxygen results in an inactive prodrug. In two cancer cell lines we show that photolysis of this compound releases panobinostat and an unexpected carboxamide analogue of panobinostat. Photolysis of Zap-Pano causes an increase in H3K9Ac and H3K18Ac, consistent with KDAC inhibition, in an oesophageal cancer cell line (OE21). Irradiation of OE21 cells in the presence of Zap-Pano results in apoptotic cell death. This compound is a useful research tool, allowing spatial and temporal control over release of panobinostat.

Keywords: KDAC; Panobinostat; hypoxia; prodrugs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Cell Death / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Dose-Response Relationship, Drug
  • Drug Screening Assays, Antitumor
  • Histone Deacetylase Inhibitors / chemical synthesis
  • Histone Deacetylase Inhibitors / chemistry
  • Histone Deacetylase Inhibitors / pharmacology*
  • Histone Deacetylases / metabolism*
  • Humans
  • Molecular Structure
  • Panobinostat / chemical synthesis
  • Panobinostat / chemistry
  • Panobinostat / pharmacology*
  • Prodrugs / chemical synthesis
  • Prodrugs / chemistry
  • Prodrugs / pharmacology*
  • Structure-Activity Relationship

Substances

  • Antineoplastic Agents
  • Histone Deacetylase Inhibitors
  • Prodrugs
  • Panobinostat
  • Histone Deacetylases