作者: Lee, Sang Wu ; Lee, So Young ; Jeon, Raok ; Kim, Yonjung ; Park, Ki Whan ; Lee, Heejin ; Kang, Jong Soon ; Kim, Jisoo ; Yu, Ji Hoon ; Kim, Yoon-Jung ; Lee, Eun ; Jeon, Yong Hyun ; Cho, Hyewon ; Kwon, So Hee ; Shin, Soojeong

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.

2024-12-01·European Journal of Medicinal Chemistry

HDAC8 as a target in drug discovery: Function, structure and design

Review

作者: Peng, Jie ; Niu, Haoqian ; Wu, Jingde ; Zhang, Xinbo ; Hao, Huabei ; Liu, Hongyan ; Liu, Xinyu ; Zhao, Qianlong ; Xue, Haoyu ; Liu, Wenjia ; Liu, Jingqian

Histone deacetylases (HDACs) have emerged as prominent therapeutic targets in drug discovery. Among the members of the HDAC family, HDAC8 exhibits distinct structural and physiological features from other members of the class Ⅰ HDACs. In addition to histones, numerous non-histone substrates such as structural maintenance of chromosomes 3 (SMC3), p53, estrogen-related receptor alpha (ERRα), etc., have been identified for HDAC8, suggesting the involvement of HDAC8 in diverse biological processes. Studies have demonstrated that HDAC8 plays essential roles in certain disease development, e.g., acute myeloid leukemia (AML), neuroblastoma, and X-Linked disorders. Despite several HDAC8 inhibitors have been discovered, only one compound has progressed to clinical studies. Recently, novel strategies targeting HDAC8 have emerged, including identifying innovative zinc-chelating groups (ZBG), developing multi-target drugs, and HDAC8 PROTACs. This review aims to summarize recent progress in developing new HDAC8 inhibitors that incorporate novel strategies and provide an overview of the clinical improvements associated with HDAC8 inhibitors.

2024-10-02·Expert Opinion on Therapeutic Patents

A patent review of histone deacetylase 8 (HDAC8) inhibitors (2013–present)

Review

作者: Jha, Tarun ; Ghosh, Balaram ; Adhikari, Nilanjan ; Banerjee, Suvankar

INTRODUCTIONThe processes and course of several fatal illnesses, such as cancer, inflammatory diseases, and neurological disorders are closely correlated with HDAC8. Therefore, novel HDAC8 inhibitors represent effective therapeutic possibilities that may help treat these conditions. To yet, there are not any such particular HDAC8 inhibitors available for sale. This review was conducted to examine recent HDAC8 inhibitors that have been patented over the last 10 years.AREAS COVEREDThis review focuses on HDAC8 inhibitor-related patents and their therapeutic applications that have been published within the last 10 years and are accessible through the Patentscope and Google Patents databases.EXPERT OPINIONA handful of HDAC8 inhibitor-related patents have been submitted over the previous 10 years, more selective, and specific HDAC8 inhibitors that are intended to treat a variety of medical diseases. This could lead to the development of novel treatment approaches that target HDAC8. Employing theoretical frameworks and experimental procedures can reveal the creation of new HDAC8 inhibitors with enhanced pharmacokinetic characteristics. A thorough understanding of the role that HDAC8 inhibitors play in cancer, including the mechanisms behind HDAC8 in other disorders is necessary.

100 项与 HDAC8 inhibitors(Zhejiang Chinese Medical University) 相关的药物交易

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