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  2. Establishing a noncanonical zinc-binding group as a selective histone deacetylase inhibitor and possible novel anticancer agent

Establishing a noncanonical zinc-binding group as a selective histone deacetylase inhibitor and possible novel anticancer agent

  • Bioorg Chem. 2025 Aug 27:165:108917. doi: 10.1016/j.bioorg.2025.108917.
Hsuan-Chun Huang 1 Tse-Yu Chen 1 Tsung-Yu Yeh 1 Min-Hsuan Yu 1 Sian-Siou Wu 1 Guang-Yi Li 1 Bo-Yu Chen 2 Miao-Hsia Lin 2 Ching-Jung Lin 1 Jui-Ling Hsu 3 Jih-Hwa Guh 4 Chao-Wu Yu 5
Affiliations

Affiliations

  • 1 School of Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan.
  • 2 Department and Graduate Institute of Microbiology, College of Medicine, National Taiwan University, Taipei, Taiwan.
  • 3 Department of Nursing, Center for Drug Research and Development, Chang Gung University of Science and Technology, Guishan, Taoyuan, Taiwan; Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan, Taiwan.
  • 4 School of Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan. Electronic address: jhguh@ntu.edu.tw.
  • 5 School of Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan. Electronic address: stifenyu@ntu.edu.tw.
Abstract

HDAC inhibitors, which have been proven to be effective for some cancers, have potential as treatments for Non-small cell lung Cancer (NSCLC). Building on the core structure of the highly selective HDAC6 Inhibitor J22352, we modified various zinc-binding groups of this inhibitor. The resulting compounds 1-8 were designed and synthesized to explore potential derivatives and assess their effects on NSCLC bioactivity. Notably, compounds 2, 7, and 8 selectively inhibited HDAC6, with IC50 values of 865.4, 145.0, and 11.9 nM, respectively. Additionally, a significant synergistic interaction was observed when benzamide 6 and ethyl hydrazine 7 were combined with the chemotherapy drug etoposide. The combination index of benzamide 6 (10 μM) with etoposide (10 μM) was 0.22, in contrast to 0.01 for ethyl hydrazine 7 (30 μM) with etoposide (10 μM). Encouragingly, ethyl hydrazine 7 also demonstrated superior bioavailability (149 %) after oral administration.

Keywords

Benzamide; Ethyl hydrazine; Histone deacetylase (HDAC); Non-hydroxamic acid histone deacetylase inhibitor (HDACi).

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