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Published on: August 10, 2017
Discovery of organosulfur-based selective HDAC8 inhibitors with anti-neuroblastoma activity
Hyewon Cho1, Eun Lee1, Jisoo Kim1
1College of Pharmacy, Sookmyung Women's University, Cheongpa-ro 47-gil 100, Yongsan-gu, Seoul, 04310, Republic of Korea.
Abstract:
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.
Insights
Researchers developed novel, selective HDAC8 inhibitors derived from ajoene, a garlic compound. These inhibitors show promise for treating neuroblastoma with reduced toxicity compared to existing therapies.
Area of Science:
- Epigenetics
- Medicinal Chemistry
- Oncology
Background:
- Histone deacetylases (HDACs) regulate gene expression and cellular functions, making them key targets for cancer therapy.
- HDAC8 is a particularly promising target for treating childhood neuroblastoma.
- Current HDAC inhibitors lack selectivity and can cause side effects, necessitating the development of novel, targeted agents.
Purpose of the Study:
- To identify novel, isoform-selective HDAC8 inhibitors with a unique zinc-binding group (ZBG).
- To explore structure-activity relationships (SAR) of sulfur-based compounds derived from ajoene.
- To evaluate the antiproliferative and in vivo efficacy of lead compounds against neuroblastoma.
Main Methods:
- Modification of ajoene, a natural compound, to create a series of sulfur-based HDAC inhibitors.
- Structure-activity relationship (SAR) studies to optimize inhibitor potency and selectivity.
- Molecular docking studies to understand the binding interactions with HDAC8.
- In vitro antiproliferative assays against neuroblastoma cell lines.
- In vivo efficacy studies in a neuroblastoma xenograft mouse model.
Main Results:
- Identification of potent and selective HDAC8 inhibitors featuring a novel ZBG.
- Compound 15c demonstrated significant antiproliferative activity (GI50 = 2 µM) against neuroblastoma cell lines.
- Docking studies provided a structural basis for the observed HDAC8 inhibitory activity.
- Compound 15c showed notable in vivo efficacy in a neuroblastoma xenograft model.
Conclusions:
- Novel sulfur-based HDAC8 inhibitors with a unique ZBG were successfully developed.
- The lead compound, 15c, exhibits potent anticancer activity against neuroblastoma both in vitro and in vivo.
- These findings highlight the potential of selective HDAC8 inhibition as a therapeutic strategy for neuroblastoma.
