Discovery of organosulfur-based selective HDAC8 inhibitors with anti-neuroblastoma activity

• Published in: European journal of pharmaceutical sciences 2024-12, Vol.203, p.106921, Article 106921
• Main Authors: Cho, Hyewon, Lee, Eun, Kim, Jisoo, Shin, Soojeong, Kim, Yoon-Jung, Lee, Heejin, Yu, Ji Hoon, Jeon, Yong Hyun, Lee, Sang Wu, Lee, So Young, Park, Ki Whan, Kang, Jong Soon, Kwon, So Hee, Kim, Yonjung, Jeon, Raok
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Cell Line, Tumor; Cell Proliferation - drug effects; Histone deacetylase 8; Histone Deacetylase Inhibitors - chemistry; Histone Deacetylase Inhibitors - pharmacology; Histone Deacetylases - metabolism; Humans; Inhibitor; Mice; Mice, Nude; Molecular Docking Simulation; Neuroblastoma; Neuroblastoma - drug therapy; Organosulfur; Repressor Proteins - antagonists & inhibitors; Structure-Activity Relationship; Sulfur Compounds - chemistry; Sulfur Compounds - pharmacology; Xenograft Model Antitumor Assays
• ISSN: 0928-0987; 1879-0720; 1879-0720
• DOI: 10.1016/j.ejps.2024.106921

•Sulfur-based selective HDAC8 inhibitors were identified by modifying ajoene.•Structure-activity relationship studies revealed selective HDAC8 inhibitors.•(Z)−1-Phenyl-7-(4-methoxyphenyl)−2,3,7-trithiahepta-4-ene-7-oxide (15c) exhibited antiproliferative activity against neuroblastoma cell lines.•15c showed significant in vivo efficacy in a neuroblastoma xenograft model. Histone deacetylases (HDACs) are important epigenetic regulators of gene expression and various cellular processes, and are potential targets for anticancer therapy. In particular, HDAC8 is a promising therapeutic target for childhood neuroblastoma. To date, five HDAC inhibitors have been approved as anticancer drugs; however, all are non-selective HDAC inhibitors with various side effects. Furthermore, many promising HDAC inhibitors incorporate hydroxamic acid as a zinc binding group (ZBG), which may be associated with toxicity. Therefore, identification of isoform-selective HDAC inhibitors with novel ZBG is crucial. Here, a series of sulfur-based selective HDAC8 inhibitors featuring a novel ZBG were identified by modifying the early hit, ajoene, a component of garlic. Structure-activity relationship studies uncovered potent and selective HDAC8 inhibitors, and docking studies provided a structural rationale for HDAC8 inhibitory activity. One of the potent compounds, (Z)-1-phenyl-7-(4-methoxyphenyl)-2,3,7-trithiahepta-4-ene-7-oxide (15c), exhibited antiproliferative activity, with a GI50 of 2 µM, against neuroblastoma cell lines. 15c also showed significant in vivo efficacy in a neuroblastoma BE(2)-C xenograft model. [Display omitted]