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.

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 reverse

SUBMITTER: Stopper D 

PROVIDER: S-EPMC11867874 | biostudies-literature | 2025 Feb

REPOSITORIES: biostudies-literature