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Optimization of 5-arylidene barbiturates as potent, selective, reversible LSD1 inhibitors for the treatment of acute promyelocytic leukemia.
Xu, Siyuan; Zhou, Chen; Liu, Rongfeng; Zhu, Qihua; Xu, Yungen; Lan, Fei; Zha, Xiaoming.
Affiliation
  • Xu S; Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Key Laboratory of Epigenetics and Metabolism, Ministry of Science and Technology, and Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, PR Ch
  • Zhou C; Department of Pharmaceutical Engineering, Department of Biomedical Engineering, Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing 210009, PR China; Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, PR China.
  • Liu R; Shanghai ChemPartner Co. Ltd., Zhangjiang Hi-Tech Park, Shanghai 201203, PR China.
  • Zhu Q; Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, PR China.
  • Xu Y; Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, PR China. Electronic address: xyg64@126.com.
  • Lan F; Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Key Laboratory of Epigenetics and Metabolism, Ministry of Science and Technology, and Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, PR Ch
  • Zha X; Department of Pharmaceutical Engineering, Department of Biomedical Engineering, Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing 210009, PR China. Electronic address: xmzha@cpu.edu.cn.
Bioorg Med Chem ; 26(17): 4871-4880, 2018 09 15.
Article in En | MEDLINE | ID: mdl-30153955
ABSTRACT
Histone lysine specific demethylase 1 (LSD1) is overexpressed in diverse hematologic disorders and recognized as a promising target for blood medicines. In this study, molecular docking-based virtual screening united with bioevaluation was utilized to identify novel skeleton of 5-arylidene barbiturate as small-molecule inhibitors of LSD1. Among the synthesized derivatives, 12a exhibited reversible and potent inhibition (IC50 = 0.41 µM) and high selectivity over the MAO-A and MAO-B. Notably, 12a strongly induced differentiation effect on acute promyelocytic leukemia NB4 cell line and distinctly escalated the methylation level on histone 3 lysine 4 (H3K4). Our findings indicate that 5-arylidene barbiturate may represent a new skeleton of LSD1 inhibitors and 12a deserve as a promising agent for the further research.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Barbiturates / Leukemia, Myeloid, Acute / Enzyme Inhibitors / Histone Demethylases / Antineoplastic Agents Type of study: Prognostic_studies Limits: Humans Language: En Journal: Bioorg Med Chem Journal subject: BIOQUIMICA / QUIMICA Year: 2018 Type: Article
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Barbiturates / Leukemia, Myeloid, Acute / Enzyme Inhibitors / Histone Demethylases / Antineoplastic Agents Type of study: Prognostic_studies Limits: Humans Language: En Journal: Bioorg Med Chem Journal subject: BIOQUIMICA / QUIMICA Year: 2018 Type: Article