Design, synthesis and biological evaluation of tetrahydroquinoline-based reversible LSD1 inhibitors

Article abstract of DOI:10.1016/j.ejmech.2020.112243

The targeted regulation of LSD1, which is highly expressed in a variety of tumor cells, is a promising cancer therapy strategy. Several LSD1 inhibitors are currently under clinical evaluation, and most of these inhibitors are irreversible. Here, we report the design, synthesis and biochemical evaluation of novel tetrahydroquinoline-based reversible LSD1 inhibitors. Compounds 18s and 18x, which are selective to LSD1 over MAO-A/B, exhibit excellent LSD1 inhibition at the molecular levels with IC₅₀ = 55 nM and 540 nM, respectively. The classic Lineweaver–Burk plots revealed that compound 18s could reversibly bind the LSD1 enzyme in a noncompetitive manner. Molecular docking was used to reveal the potential binding-mode of the compounds and interpret the structure-activity relationships. Furthermore, compounds 18s and 18x significantly inhibited proliferation (IC₅₀ = 1.13 μM and 1.15 μM, respectively) and induced apoptosis in MGC-803 cells with high expression of LSD1. Compound 18x showed acceptable liver microsomal stability. Meanwhile, 18x did not appear to inhibit CYPs at 10 μM in vitro. Remarkably, the oral administration of compound 18x can inhibit the growth of MGC-803 xenograft tumors without significant side effects. Our findings suggest that tetrahydroquinoline-based LSD1 inhibitors deserve further investigation for the treatment of LSD1 overexpressing cancer.

Full text of DOI:10.1016/j.ejmech.2020.112243

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Design, synthesis and biological evaluation of tetrahydroquinoline-based reversible
LSD1 inhibitors
Xinran Wang, Cai Zhang, Xiangyu Zhang, Jiangkun Yan, Jiming Wang, Qinwen
Jiang, Liyu Zhao, Dongmei Zhao, Maosheng Cheng
PII:
S0223-5234(20)30210-5
DOI:
https://doi.org/10.1016/j.ejmech.2020.112243
EJMECH 112243
Reference:
To appear in: European Journal of Medicinal Chemistry
Received Date: 7 January 2020
Revised Date: 8 March 2020
Accepted Date: 16 March 2020
Please cite this article as: X. Wang, C. Zhang, X. Zhang, J. Yan, J. Wang, Q. Jiang, L. Zhao, D.
Zhao, M. Cheng, Design, synthesis and biological evaluation of tetrahydroquinoline-based reversible
LSD1 inhibitors, European Journal of Medicinal Chemistry (2020), doi: https://doi.org/10.1016/
j.ejmech.2020.112243.
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Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
Design, synthesis and biological evaluation of
tetrahydroquinoline-based reversible LSD1 inhibitors
a
b
Xinran Wang , Cai Zhang , Xiangyu Zhang a, Jiangkun Yan a, Jiming Wang a, Qinwen Jiang a,
Liyu Zhao a, Dongmei Zhao a,* and Maosheng Cheng a
a Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, School
of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe
District, Shenyang, 110016, China
b The School of Life Science and Biopharmaceutical, Shenyang Pharmaceutical University, 103
Wenhua Road, Shenhe District, Shenyang, 110016, China
* Correspondence: medchemzhao@163.com; Tel.: +86-24-4352-0219
Abstract
The targeted regulation of LSD1, which is highly expressed in a variety of tumor cells, is a
promising cancer therapy strategy. Several LSD1 inhibitors are currently under clinical evaluation,
and most of these inhibitors are irreversible. Here, we report the design, synthesis and biochemical
evaluation of novel tetrahydroquinoline-based reversible LSD1 inhibitors. Compounds 18s and
18x, which are selective to LSD1 over MAO-A/B, exhibit excellent LSD1 inhibition at the
molecular levels with IC50 = 55 nM and 540 nM, respectively. The classic Lineweaver–Burk plots
revealed that compound 18s could reversibly bind the LSD1 enzyme in a noncompetitive manner.
Molecular docking was used to reveal the potential binding-mode of the compounds and interpret
the structure-activity relationships. Furthermore, compounds 18s and 18x significantly inhibited
proliferation (IC50 = 1.13 μM and 1.15 μM, respectively) and induced apoptosis in MGC-803 cells
with high expression of LSD1. Compound 18x showed acceptable liver microsomal stability.
Meanwhile, 18x did not appear to inhibit CYPs at 10 μM in vitro. Remarkably, the oral
administration of compound 18x can inhibit the growth of MGC-803 xenograft tumors without
significant side effects. Our findings suggest that tetrahydroquinoline-based LSD1 inhibitors
deserve further investigation for the treatment of LSD1 overexpressing cancer.
Keywords:
LSD1; Tetrahydroquinoline; Reversible inhibitors; Molecular docking;
Structure-activity relationships

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1. Introduction
Histone modifications are among the most investigated modulators in posttranslational
modifications in epigenetics. Differing from acetylation, phosphorylation and ubiquitination,
histone methylation was originally recognized as an irreversible alteration until lysine specific
demethylase 1 (LSD1) was reported by Shi and co-workers in 2004[1]. This landmark discovery
resulted in an upsurge of research investigating LSD1 in cancers and other diseases, such as viral
infections and cardiovascular and neurodegenerative disorders.
LSD1, which is located in the cell nucleus, could specifically wipe mono- and di-methyl
modification of histone H3K4 or H3K9 with the aid of flavine adenine dinucleotide (FAD). A high
expression of LSD1 is associated with the occurrence and development of various cancer cells,
such as lung cancer[2], acute myeloid leukemia[3], lymphoid neoplasm[4], prostate cancer[5], bladder
cancer and ER-negative breast cancer cells[6]. Moreover, the close relationship between LSD1 and
a poor prognosis of tumors has also been investigated[7], and LSD1 has been identified by
researchers as a potential therapeutic target since its discovery.
Numerous LSD1 inhibitors bearing various scaffolds have been reported[8], and most such
inhibitors exhibit superior inhibitory activity. To date, several LSD1 inhibitors have exhibited
preeminent activity in clinical trials. Vafidemstat/ORY-2001 (Figure 1) is currently under
investigation in phase clinical studies (NCT03867253) for Alzheimer’s type dementia, and the
aim of this double-blind, placebo-controlled, randomized clinical study, which will be completed
by November 2020, is to evaluate the safety, tolerability and preliminary efficacy of vafidemstat in
patients with Alzheimer's disease. The efficacy of iadademstat/ORY-1001 (3) alone or in
combination with other anticancer agents has been evaluated in patients with acute myeloid
leukemia and small cell lung cancer, and a clinical study (NCT02913443) currently evaluating the
safety and tolerability of ORY-1001 in patients with small-cell lung cancer is ongoing.
GSK-2879552 (2), which is another TCP-based LSD1 inhibitor, is no longer under clinical
development which was terminated because the risk benefit in relapsed refractory SCLC does not
favor continuation of the study. In 2018, Oryzon began a phase Ⅱ clinical study of the safety and
efficacy of ORY-2001 (4) in patients with episodes of aggressiveness, which is still being
evaluated. Phase II clinical study of IMG-7289 (5) in patients with myelofibrosis is under way to
investigate the safety, efficacy and pharmacokinetic properties of the drug (NCT03136185).
In addition, several phase Ⅱclinical studies of IMG-7289 in cancer and hematological diseases
are in the pipeline. Interestingly, SP-2577 (6), which is a reversible LSD1 inhibitor, was developed
at the University of Utah, and phase I clinical trials at Salarius Pharmaceuticals for the treatment
of Ewing sarcoma (NCT03600649) and solid tumors (NCT03895684) are ongoing. Two phase I
clinical studies of CC-90011 (7) are being conducted, one exploring the safety and efficacy of
CC-90011 in patients with solid tumors (NCT02875223) and the other investigating the safety,
tolerability and efficacy of CC-90011 in combination with Cisplatin and Etoposide in small cell
lung cancer (NCT03850067). In recent years, the development of reversible LSD1 inhibitors has
been in full swing, and many structures have been reported[9-14]. New mechanisms of LSD1 in
tumor therapy have been revealed, and the idea of combining LSD1 inhibitors with other drugs for
cancer treatment has also been reported[15-27]. Throughout the development of LSD1
inhibitors[28-33], only a few reversible inhibitors are worth further promotion compared to covalent
inhibitors. Therefore, the development of reversible inhibitors with novel structures and superior
pharmaceutical properties has become an epigenetic force in the development of LSD1 inhibitors.