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<p>Histone deacetylase (HDAC) inhibitors represent a promising class of anti-cancer agents that play a key role in both epigenetic and non-epigenetic regulation, leading to cancer cell death, apoptosis, and cell cycle arrest. This study synthesized novel bicyclic hydroxamic acid derivatives and evaluated their inhibitory and selectivity activity against class I and IIb HDACs. Our findings demonstrate that Compound <b>2e</b> specifically inhibits HDAC10 with high selectivity over HDAC6, while shows no significant impact on class I HDACs. Compound <b>2a</b> exhibited the most potant inhibitory activity against HDAC10, with IC<sub>50</sub> 0.41 ± 0.02 nM. In contrast, Compound <b>2f</b> revealed a preference toward HDAC6, with an IC<sub>50</sub> value of 2.5 ± 0.3 nM. Compounds <b>2c</b> and <b>2d</b> demonstrated high selectivity toward class IIb over class I HDACs. Docking and molecular dynamics studies revealed that compound <b>2a</b> fits well into the active site of HDAC10, forming stable and strong interactions with key residues F204, D94, W205, and E274 in HDAC10. In addition, we assessed the anti-proliferative activity these compounds against a panel of four human solid tumor cell lines. To evaluate their selectivity, non-cancerous kidney cell lines (LLC-PK1 and VERO) were employed to determine the effects of these compounds on normal cell proliferation.</p>

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Novel selective indole based histone deacetylase 10 inhibitors as anticancer therapeutics

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年9月26日

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  • Amer H. Tarawneh,
  • Salah A. Al-Trawneh,
  • Talha Z. Yesiloglu,
  • Matthes Zessin,
  • Dina Robaa,
  • Cyril Barinka,
  • Mike Schutkowski,
  • Wolfgang Sippl,
  • Samir A. Ross

摘要

Histone deacetylase (HDAC) inhibitors represent a promising class of anti-cancer agents that play a key role in both epigenetic and non-epigenetic regulation, leading to cancer cell death, apoptosis, and cell cycle arrest. This study synthesized novel bicyclic hydroxamic acid derivatives and evaluated their inhibitory and selectivity activity against class I and IIb HDACs. Our findings demonstrate that Compound 2e specifically inhibits HDAC10 with high selectivity over HDAC6, while shows no significant impact on class I HDACs. Compound 2a exhibited the most potant inhibitory activity against HDAC10, with IC50 0.41 ± 0.02 nM. In contrast, Compound 2f revealed a preference toward HDAC6, with an IC50 value of 2.5 ± 0.3 nM. Compounds 2c and 2d demonstrated high selectivity toward class IIb over class I HDACs. Docking and molecular dynamics studies revealed that compound 2a fits well into the active site of HDAC10, forming stable and strong interactions with key residues F204, D94, W205, and E274 in HDAC10. In addition, we assessed the anti-proliferative activity these compounds against a panel of four human solid tumor cell lines. To evaluate their selectivity, non-cancerous kidney cell lines (LLC-PK1 and VERO) were employed to determine the effects of these compounds on normal cell proliferation.