Discovery and synthesis of novel indole derivatives-containing 3-methylenedihydrofuran-2(3H)-one as irreversible LSD1 inhibitors

Hong-Min Liu; Feng-Zhi Suo; Xiao-Bo Li; Ying-Hua You; Chun-Tao Lv; Chen-Xing Zheng; Guo-Chen Zhang; Yue-Jiao Liu; Wen-Ting Kang; Yi-Chao Zheng; Hai-Wei Xu

doi:10.1016/j.ejmech.2019.04.065

Discovery and synthesis of novel indole derivatives-containing 3-methylenedihydrofuran-2(3H)-one as irreversible LSD1 inhibitors

Eur J Med Chem. 2019 Aug 1:175:357-372. doi: 10.1016/j.ejmech.2019.04.065. Epub 2019 Apr 29.

Authors

Affiliations

¹ Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, Co-innovation Center of Henan Province for New Drug R & D and Preclinical Safety, School of Pharmaceutical Science, Institute of Drug Discovery and Development, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan, 450001, China.
² Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, Co-innovation Center of Henan Province for New Drug R & D and Preclinical Safety, School of Pharmaceutical Science, Institute of Drug Discovery and Development, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan, 450001, China; National Center for International Research of Micro-nano Molding Technology of Henan Province, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan, 450001, China. Electronic address: yichaozheng@zzu.edu.cn.
³ Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, Co-innovation Center of Henan Province for New Drug R & D and Preclinical Safety, School of Pharmaceutical Science, Institute of Drug Discovery and Development, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan, 450001, China. Electronic address: xhwei01@zzu.edu.cn.

PMID: 31096156
DOI: 10.1016/j.ejmech.2019.04.065

Abstract

Lysine-specific demethylase 1 (LSD1), demethylase against mono- and di - methylated histone3 lysine 4, has emerged as a promising target in oncology. More specifically, it has been demonstrated as a key promoter in acute myeloid leukemia (AML), and several LSD1 inhibitors have already entered into clinical trials for the treatment of AML. In this paper, a series of new indole derivatives were designed and synthesized based on a lead compound obtained by a high-throughput screening with our in-house compound library. Among the synthetic compounds, 9e was characterized as a potent LSD1 inhibitor with an IC₅₀ of 1.230 μM and can inhibit the proliferation of THP-1 cells effectively. And most importantly, this is the first irreversible LSD1 inhibitor that is not derived from monoamine oxidase inhibitors. Hence, the discovery of 9e may serve as a proof of concept work for AML treatment.

Keywords: Indole; Inhibitor; Irreversible; LSD1; Lactone.

MeSH terms

Cell Line
Cell Proliferation / drug effects
Drug Discovery*
Enzyme Inhibitors / chemical synthesis*
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / metabolism
Enzyme Inhibitors / pharmacology*
Furans / chemistry
High-Throughput Screening Assays
Histone Demethylases / antagonists & inhibitors*
Histone Demethylases / metabolism
Humans
Indoles / chemical synthesis*
Indoles / chemistry
Indoles / metabolism
Indoles / pharmacology*
Inhibitory Concentration 50
Leukemia, Myeloid, Acute / pathology
Recombinant Proteins / drug effects
Recombinant Proteins / metabolism
Structure-Activity Relationship

Substances

Enzyme Inhibitors
Furans
Indoles
Recombinant Proteins
Histone Demethylases
KDM1A protein, human
furan