Design, synthesis and in vitro evaluation of stilbene derivatives as novel LSD1 inhibitors for AML therapy

Yingchao Duan; Wenping Qin; Fengzhi Suo; Xiaoyu Zhai; Yuanyuan Guan; Xiaojuan Wang; Yichao Zheng; Hongmin Liu

doi:10.1016/j.bmc.2018.10.037

Design, synthesis and in vitro evaluation of stilbene derivatives as novel LSD1 inhibitors for AML therapy

Bioorg Med Chem. 2018 Dec 15;26(23-24):6000-6014. doi: 10.1016/j.bmc.2018.10.037. Epub 2018 Oct 29.

Authors

Yingchao Duan¹, Wenping Qin¹, Fengzhi Suo², Xiaoyu Zhai¹, Yuanyuan Guan¹, Xiaojuan Wang³, Yichao Zheng⁴, Hongmin Liu⁵

Affiliations

¹ School of Pharmacy, Xinxiang Medical University, Xinxiang, Henan 453003, 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, Institute of Drug Discovery and Development, School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, China.
³ College of Chemistry and Chemical Engineering, Shangqiu Normal University, Shangqiu, Henan 476000, China.
⁴ 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, Institute of Drug Discovery and Development, School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, China. Electronic address: yichaozheng@zzu.edu.cn.
⁵ 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, Institute of Drug Discovery and Development, School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, China. Electronic address: liuhm@zzu.edu.cn.

PMID: 30448189
DOI: 10.1016/j.bmc.2018.10.037

Abstract

LSD1 is implicated in a number of malignancies and has emerged as an exciting target. As part of our sustained efforts to develop novel reversible LSD1 inhibitors for epigenetic therapy of cancers, in this study, we reported a series of stilbene derivatives and evaluated their LSD1 inhibitory activities, obtaining several compounds as potent LSD1 inhibitors with IC₅₀ values in submicromolar range. Enzyme kinetics studies and SPR assay suggested that compound 8c, the most active LSD1 inhibitor (IC₅₀ = 283 nM), potently inhibited LSD1 in a reversible and FAD competitive manner. Consistent with the kinetics data, molecular docking showed that compound 8c can be well docked into the FAD binding site of LSD1. Flow cytometry analysis showed that compound 8c was capable of up-regulating the expression of the surrogate cellular biomarker CD86 in THP-1 human leukemia cells, suggesting the ability to block LSD1 activity in cells. Compound 8c showed good inhibition against THP-1 and MOLM-13 cells with IC₅₀ values of 5.76 and 8.34 μM, respectively. Moreover, compound 8c significantly inhibited colony formation of THP-1 cells dose dependently.

Keywords: AML; Lysine-specific demethylase 1; Stilbene; Synthesis.

Publication types

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

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Proliferation / drug effects
Cell Survival / drug effects
Dose-Response Relationship, Drug
Drug Design*
Drug Screening Assays, Antitumor
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Histone Demethylases / antagonists & inhibitors*
Histone Demethylases / metabolism
Humans
Leukemia, Myeloid, Acute / drug therapy*
Leukemia, Myeloid, Acute / metabolism
Leukemia, Myeloid, Acute / pathology
Molecular Docking Simulation
Molecular Structure
Stilbenes / chemical synthesis
Stilbenes / chemistry
Stilbenes / pharmacology*
Structure-Activity Relationship
THP-1 Cells

Substances

Antineoplastic Agents
Enzyme Inhibitors
Stilbenes
Histone Demethylases
KDM1A protein, human