Optimization of 5-arylidene barbiturates as potent, selective, reversible LSD1 inhibitors for the treatment of acute promyelocytic leukemia

Siyuan Xu; Chen Zhou; Rongfeng Liu; Qihua Zhu; Yungen Xu; Fei Lan; Xiaoming Zha

doi:10.1016/j.bmc.2018.08.026

Optimization of 5-arylidene barbiturates as potent, selective, reversible LSD1 inhibitors for the treatment of acute promyelocytic leukemia

Bioorg Med Chem. 2018 Sep 15;26(17):4871-4880. doi: 10.1016/j.bmc.2018.08.026. Epub 2018 Aug 22.

Authors

Siyuan Xu¹, Chen Zhou², Rongfeng Liu³, Qihua Zhu⁴, Yungen Xu⁵, Fei Lan⁶, Xiaoming Zha⁷

Affiliations

¹ 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 China.
² 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.
³ Shanghai ChemPartner Co. Ltd., Zhangjiang Hi-Tech Park, Shanghai 201203, PR China.
⁴ Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, PR China.
⁵ Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, PR China. Electronic address: xyg64@126.com.
⁶ 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 China. Electronic address: fei_lan@fudan.edu.cn.
⁷ 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.

PMID: 30153955
DOI: 10.1016/j.bmc.2018.08.026

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.

Keywords: 5-Arylidene barbiturate; LSD1; Leukemia; Reversible; Selective.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / pharmacology
Antineoplastic Agents / therapeutic use*
Barbiturates / chemistry
Barbiturates / pharmacology*
Cell Line, Tumor
DNA Methylation
Enzyme Inhibitors / pharmacology
Enzyme Inhibitors / therapeutic use*
Histone Demethylases / antagonists & inhibitors*
Humans
Inhibitory Concentration 50
Leukemia, Myeloid, Acute / drug therapy*
Leukemia, Myeloid, Acute / pathology
Molecular Docking Simulation
Spectrum Analysis / methods

Substances

Antineoplastic Agents
Barbiturates
Enzyme Inhibitors
Histone Demethylases
KDM1A protein, human