Exploring Alternative Zinc-Binding Groups in Histone Deacetylase (HDAC) Inhibitors Uncovers DS-103 as a Potent Ethylhydrazide-Based HDAC Inhibitor with Chemosensitizing Properties

  • J Med Chem. 2025 Feb 27;68(4):4426-4452. doi: 10.1021/acs.jmedchem.4c02373.
Daniel Stopper  1 ,  Lukas Biermann  2 ,  Paris R Watson  3 ,  Jingyu Li  2 ,  Beate König  1 ,  Matthew N Gaynes  3 ,  Lais Pessanha de Carvalho  4 ,  Jana Klose  5 ,  Maria Hanl  1 ,  Alexandra Hamacher  2 ,  Linda Schäker-Hübner  1 ,  Daniel Ramsbeck  5 ,  Jana Held  4  6  7 ,  David W Christianson  3 ,  Matthias U Kassack  2 ,  Finn K Hansen  1
Affiliations
  • 1. Department of Pharmaceutical and Cell Biological Chemistry, Pharmaceutical Institute, University of Bonn, 53121 Bonn, Germany.
  • 2. Institute of Pharmaceutical and Medicinal Chemistry, University of Düsseldorf, 40225 Düsseldorf, Germany.
  • 3. Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, 231 South 34th Street, Philadelphia, Pennsylvania 19104-6323, United States.
  • 4. Institute of Tropical Medicine, University of Tübingen, 72074 Tübingen, Germany.
  • 5. Department of Applied Biosciences and Process Technology, Anhalt University of Applied Sciences, 06366 Köthen, Germany.
  • 6. German Center for Infection Research, Partner Site Tübingen, 72074 Tübingen, Germany.
  • 7. Centre de Recherches Médicales de Lambaréné, BP: 242 Lambaréné, Gabon.
PMID: 39946728 DOI: 10.1021/acs.jmedchem.4c02373
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.

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