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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.

Original publication

DOI

10.1002/cmdc.202100403

Type

Journal article

Journal

ChemMedChem

Publication Date

14/12/2021

Volume

16

Pages

3691 - 3700

Keywords

KDAC, Panobinostat, hypoxia, prodrugs, Antineoplastic Agents, Apoptosis, Cell Death, Cell Line, Tumor, Cell Proliferation, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, Histone Deacetylase Inhibitors, Histone Deacetylases, Humans, Molecular Structure, Panobinostat, Prodrugs, Structure-Activity Relationship