Exploring AlternativeZinc-Binding Groups in HistoneDeacetylase (HDAC) Inhibitors Uncovers <b>DS-103</b> as a PotentEthylhydrazide-Based HDAC Inhibitor with Chemosensitizing Properties

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 <b>20</b> (<b>DS-103</b>) proved to be the most effective compound in these primary screenings. <b>DS-103</b> showed nanomolar inhibition of class I HDACs and of HDAC6 (class IIb). To further investigate the binding mode of <b>DS-103</b>, a crystal structure of <b>DS-103</b> in complex with HDAC6 was obtained, which represents the first reported crystal structure of an alkylhydrazide in complex with an HDAC enzyme. Importantly, <b>DS-103</b> 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.