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.
- 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: [email protected].
- 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: [email protected].
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.