Exploring Alternative Zinc-Binding Groups in Histone Deacetylase (HDAC) Inhibitors Uncovers <b>DS-103</b> as a Potent Ethylhydrazide-Based HDAC Inhibitor with Chemosensitizing Properties
Daniel Stopper, Lukas Biermann, P. R. Watson, Jingyu Li, Beate König, Matthew N. Gaynes, Laís Pessanha de Carvalho, Jana Klose, Maria Hanl, Alexandra Hamacher, Linda Schäker‐Hübner, Daniel Ramsbeck, Jana Held, David W. Christianson, Matthias U. Kassack, Finn K. Hansen
Abstract
In this work, we synthesized a series of peptoid-based histone deacetylase (HDAC) inhibitors with variations in the linker region and zinc-binding groups. All compounds were investigated for their HDAC inhibition, antiplasmodial activity, and cytotoxicity against native and cisplatin-resistant carcinoma cell lines. The ethylhydrazide 20 ( DS-103 ) proved to be the most effective compound in these primary screenings. DS-103 showed nanomolar inhibition of class I HDACs and of HDAC6 (class IIb). To further investigate the binding mode of DS-103, a crystal structure of DS-103 in complex with HDAC6 was obtained, which represents the first reported crystal structure of an alkylhydrazide in complex with an HDAC enzyme. Importantly, DS-103 completely reversed cisplatin resistance in two different platinum-resistant solid cancer cell lines and demonstrated strong synergism with cisplatin. The synergistic anticancer effects are mediated by increased DNA damage and p21 expression, resulting in caspase-mediated apoptosis and cell death.