Hydrazide-based class I HDAC inhibitors with HDAC3 preference completely reverse chemoresistance in a synergistic manner in platinum-resistant solid cancer cells

02 August 2024, Version 2
This content is a preprint and has not undergone peer review at the time of posting.

Abstract

In this work, we have synthesized a set of peptoid based HDACi with a substituted hydrazide moiety as zinc-binding group. Subsequently, all compounds were evaluated in biochemical HDAC inhibition assays and for their antiproliferative activity against native and cisplatin-resistant cancer cell lines. The hydrazide derivatives with a propyl or butyl substituent (compounds 5 and 6) emerged as the most potent class I HDAC selective inhibitors (HDAC1-3), with low nanomolar IC50 values and a notable preference for HDAC3. Further, compounds 5 and 6 outperformed entinostat in cytotoxicity assays and were able to reverse chemoresistance in cisplatin-resistant A2780 (ovarian) and Cal27 (head-neck) cancer cell lines. Moreover, the hydrazide derivatives 5 and 6 showed strong synergism with cisplatin (combination indices < 0.2), again outperforming entinostat, and increased DNA damage, p21, and pro-apoptotic BIM expression, leading to caspase-mediated apoptosis and cell death. Thus, compounds 5 and 6 represent promising lead structures for developing new HDACi capable of reversing chemoresistance in cisplatin resistant cancer cells.

Keywords

Epigenetics
Cancer
HDAC
Chemoresistance
Cisplatin

Supplementary materials

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Supporting Information
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Supplemental Figures and Tables, NMR spectra, and HPLC traces
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