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
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.
Authors
- Jana Held (ORCID: https://orcid.org/0000-0002-7970-1429)
- David W. Christianson (ORCID: https://orcid.org/0000-0002-0194-5212)
- Linda Schäker‐Hübner (ORCID: https://orcid.org/0000-0001-7734-124X)
- Beate König
- P. R. Watson (ORCID: https://orcid.org/0000-0002-6990-525X)
- Jingyu Li (ORCID: https://orcid.org/0000-0002-5160-1100)
- Finn K. Hansen (ORCID: https://orcid.org/0000-0001-9765-5975)
- Jana Klose
- Daniel Ramsbeck (ORCID: https://orcid.org/0000-0002-4966-142X)
- Alexandra Hamacher
- Matthias U. Kassack (ORCID: https://orcid.org/0000-0002-9094-8481)
- Maria Hanl
- Laís Pessanha de Carvalho (ORCID: https://orcid.org/0000-0002-3857-5462)
- Matthew N. Gaynes (ORCID: https://orcid.org/0000-0001-9649-601X)
- Daniel Stopper (ORCID: https://orcid.org/0009-0009-0610-7830)
- Lukas Biermann
Institutions
- University of Bonn (DE)
- Research Institute for Tropical Medicine (PH)
- Anhalt University of Applied Sciences (DE)
- Centre de Recherche Médicales de Lambaréné (GA)
- German Center for Infection Research (DE)
- Heinrich Heine University Düsseldorf (DE)
- University of Pennsylvania (US)
- University of Tübingen (DE)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-02-13
- DOI
- https://doi.org/10.1021/acs.jmedchem.4c02373
- Citations
- 11
- Primary Topic
- Histone Deacetylase Inhibitors Research
- Type
- article
- Field-Weighted Citation Impact
- 8.87
Funders
- Deutsche Forschungsgemeinschaft
- National Institutes of Health