2. Academic Validation
  3. Design, synthesis and evaluation of structural optimization derived HDAC6 isoform-selective inhibitor

Design, synthesis and evaluation of structural optimization derived HDAC6 isoform-selective inhibitor

  • Bioorg Chem. 2025 Jul 1:161:108562. doi: 10.1016/j.bioorg.2025.108562.
Chen Chen 1,  Xiaochun Ma 2,  Yichao Wan 3,  Yidong Zhong 4,  Xuben Hou 5,  Hao Fang 6,  Tao Liang 7
Affiliations

Affiliations

  • 1 Shandong Chengchuang Blue Sea Pharmaceutical Technology Co., Ltd., Jinan,250100, PR China.
  • 2 Department of Stomatology, I.M. Sechenov First Moscow State Medical University, Moscow, 119991, Russia.
  • 3 Key Laboratory of Theoretical Organic Chemistry and Functional Molecule, Ministry of Education, School of Chemistry and Chemical Engineering, Hunan University of Science and Technology, Xiangtan, Hunan 411201, PR China.
  • 4 Department of Pharmacy, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan 250117, PR China.
  • 5 Shandong Key Laboratory of Druggability Optimization and Evaluation for Lead Compounds, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan 250012, Shandong, PR China.
  • 6 Shandong Key Laboratory of Druggability Optimization and Evaluation for Lead Compounds, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan 250012, Shandong, PR China. Electronic address: haofangcn@sdu.edu.cn.
  • 7 Department of Pharmacy, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan 250117, PR China. Electronic address: sdtliangtao@163.com.
PMID: 40347770 DOI: 10.1016/j.bioorg.2025.108562
Abstract

In stark contrast to Other HDAC isoforms, deletion or inhibition of HDAC6 suppresses cell proliferation without lethality or defective phenotypes, thereby establishing HDAC6 as a compelling anti-cancer target. In pursuit of safe and effective anti-cancer chemotherapy, we preformed three-round structural optimization and developed several potent HDAC6-selective inhibitors. Among these, HDSI-18 exhibited remarkable inhibitory activity (IC50 = 1.6 nM) and exceptional isoform selectivity (over 975-fold) against HDAC6. Further biological evaluations highlighted the promising properties of HDSI-18 in terms of anti-proliferative activity, mitochondrial depolarization, Caspase-3 activation, Apoptosis induction and druggability (both in vivo and in vitro). This study demonstrated a paradigm for the rational structural optimization of HDAC6 selective inhibitors, which may serve as a beacon for the development of more promiscuous compounds.

Keywords

Anti-tumor; Apoptosis; HDAC6; Isoform-selective inhibitor; Structural optimization.

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