Exploring Alternative Zinc-Binding Groups in Histone Deacetylase (HDAC) Inhibitors Uncovers DS-103 as a Potent Ethylhydrazide-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 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.

Excited to share our latest research which is now out in #JMedChem @pubs.acs.org

A huge thank you to my amazing co-authors and collborators! 🚀

pubs.acs.org/doi/10.1021/...

Development of Ethyl Hydrazide-Based Selective Histone Deacetylase 6 (HDAC6) PROTACs

Authors: Daniel Stopper, Irina Honin, Felix Feller, Finn Kristian Hansen
DOI: 10.26434/chemrxiv-2025-8dblf

Development of Ethyl Hydrazide-Based Selective Histone Deacetylase 6 (HDAC6) PROTACs Histone deacetylases (HDACs) are promising targets for epigenetic drug discovery. Additionally, targeted degradation of HDACs has emerged as a novel approach in medicinal chemistry and chemical biolog...

I am very happy to share our new paper on the development of selective HDAC6 PROTACs utilizing an unselective ethyl hydrazide-based HDAC ligand. Congrats to all co-authors especially to Irina for the shared first-authorship! chemrxiv.org/engage/chemr...

Multicomponent syntheses enable the discovery of novel quisinostat-derived chemotypes as histone deacetylase inhibitors In this study, we synthesized and evaluated novel histone deacetylase (HDAC) inhibitors derived from the clinical candidate quisinostat. A library of …

Since #chemsky is really taking off now, I am very happy to share our new paper on the multicomponent synthesis of quisinostat analogs as antiplasmodial and anticancer #HDAC inhibitors. Thanks to everyone involved in this project!

www.sciencedirect.com/science/arti...