9dm6

Publication Abstract from PubMed

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.

Exploring Alternative Zinc-Binding Groups in Histone Deacetylase (HDAC) Inhibitors Uncovers DS-103 as a Potent Ethylhydrazide-Based HDAC Inhibitor with Chemosensitizing Properties.,Stopper D, Biermann L, Watson PR, Li J, Konig B, Gaynes MN, Pessanha de Carvalho L, Klose J, Hanl M, Hamacher A, Schaker-Hubner L, Ramsbeck D, Held J, Christianson DW, Kassack MU, Hansen FK J Med Chem. 2025 Feb 13. doi: 10.1021/acs.jmedchem.4c02373. PMID:39946728^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.