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

Wang, Xinran; Zhang, Cai; Zhang, Xiangyu; Yan, Jiangkun; Wang, Jiming; Jiang, Qinwen; Zhao, Liyu; Zhao, Dongmei; Cheng, Maosheng

doi:10.1016/j.ejmech.2020.112243

Cited by 33 publications

(18 citation statements)

References 44 publications

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“…In 2020, Wang et al designed and synthesized tetrahydroquinoline-based novel reversible LSD1 inhibitors (Figure C) . Among these compounds, the two most active compounds 55 and 56 exhibited excellent LSD1 inhibitory potency with IC 50 values of 50 nM and 540 nM, respectively.…”

Section: Reversible Lsd1 Inhibitorsmentioning

confidence: 99%

“…In addition, these hybrids may exhibit different and/or synergistic effects, increased selectivity, and reduced adverse effects. Molecular hybridization has also been used as an important tool for designing new prototypes of innovative drugs [104]. , As mentioned in the main text, our group has successfully applied molecular hybridization strategies to obtain many highly active and selective pyrimidine-triazole hybrid compounds. ,− Moreover, the development of dual inhibitors and the combination strategy of LSD1 inhibitors with other therapeutics may have great potential for cancer therapy.…”

Section: Summary and Perspectivesmentioning

confidence: 99%

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Reversible Lysine Specific Demethylase 1 (LSD1) Inhibitors: A Promising Wrench to Impair LSD1

et al. 2021

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As a flavin adenine dinucleotide (FAD)-dependent monoamine oxidase, lysine specific demethylase 1 (LSD1/KDM1A) functions as a transcription coactivator or corepressor to regulate the methylation of histone 3 lysine 4 and 9 (H3K4/9), and it has emerged as a promising epigenetic target for anticancer treatment. To date, numerous inhibitors targeting LSD1 have been developed, some of which are undergoing clinical trials for cancer therapy. Although only two reversible LSD1 inhibitors CC-90011 and SP-2577 are in the clinical stage, the past decade has seen remarkable advances in the development of reversible LSD1 inhibitors. Herein, we provide a comprehensive review about structures, biological evaluation, and structure–activity relationship (SAR) of reversible LSD1 inhibitors.

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Section: Reversible Lsd1 Inhibitorsmentioning

confidence: 99%

Section: Summary and Perspectivesmentioning

confidence: 99%

Reversible Lysine Specific Demethylase 1 (LSD1) Inhibitors: A Promising Wrench to Impair LSD1

et al. 2021

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“…LSD1 belongs to the flavin adenine dinucleotide-dependent amine oxidase family, and it is similar to other flavin-dependent amine oxidases, including MAOs. 13 Therefore, eupalinilide B was assessed for selectivity between LSD1 and MAO-A/B. From the results in Figure 4 , eupalinilide B at 1000 nM inhibited LSD1, MAO-A, and MAO-B activity with inhibitory rates of 78%, 15%, and 16.7%, respectively.…”

Section: Resultsmentioning

confidence: 99%

Eupalinilide B as a novel anti-cancer agent that inhibits proliferation and epithelial–mesenchymal transition in laryngeal cancer cells

Jiang

Zhang

2022

J Int Med Res

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Objective To investigate the anti-cancer effects and potential mechanisms of eupalinilide B in laryngeal cancer cells. Methods Laryngeal cancer cell lines were selected to study the anti-tumor effects of eupalinilide B in vitro and in vivo. Lysine-specific demethylase 1 (LSD1) activity was assessed in vitro and dialysis experiments were performed to identify the anti-tumor target of the drug. Results Eupalinilide B concentration-dependently inhibited the proliferation of laryngeal cancer cells, exhibiting potent inhibitory activity against TU686 (IC50 = 6.73 µM), TU212 (IC50 = 1.03 µM), M4e (IC50 = 3.12 µM), AMC-HN-8 (IC50 = 2.13 µM), Hep-2 (IC50 = 9.07 µM), and LCC cells (IC50 = 4.20 µM). Subsequent target verification experiments demonstrated that eupalinilide B selectively and reversibly inhibited LSD1. Furthermore, eupalinilide B, as a natural product, suppressed epithelial–mesenchymal transition in TU212 cells. An in vivo experiment further indicated that eupalinilide B could significantly reduce the growth of tumors in TU212 xenograft mouse models. Conclusions Eupalinilide B might be a novel LSD1 inhibitor for treating laryngeal cancer.

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“…Potent reversible inhibitors with excellent selectivity against MAO-A/B been developed, reaching biochemical IC 50 = 80 nM and cellular IC 50 Accepted Article of 1.3 µM (GSK354) [147]. Reversible tetrahydroquinoline inhibitors of LSD1 have also been developed [148] and several LSD1 inhibitors are currently undergoing clinical trials for cancer therapy [149] (Table 6).…”

Section: Demethylasesmentioning

confidence: 99%

Therapeutic targeting of chromatin: status and opportunities

Siklos

Kubicek

2021

The FEBS Journal

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The molecular characterization of mechanisms underlying transcriptional control and epigenetic inheritance since the 1990s has paved the way for the development of targeted therapies that modulate these pathways. In the past two decades, cancer genome sequencing approaches have uncovered a plethora of mutations in chromatin modifying enzymes across tumor types, and systematic genetic screens have identified many of these proteins as specific vulnerabilities in certain cancers. Now is the time when many of these basic and translational efforts start to bear fruit and more and more chromatin‐targeting drugs are entering the clinic. At the same time, novel pharmacological approaches harbor the potential to modulate chromatin in unprecedented fashion, thus generating entirely novel opportunities. Here, we review the current status of chromatin targets in oncology and describe a vision for the epigenome‐modulating drugs of the future.

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

Cited by 33 publications

References 44 publications

Reversible Lysine Specific Demethylase 1 (LSD1) Inhibitors: A Promising Wrench to Impair LSD1

Reversible Lysine Specific Demethylase 1 (LSD1) Inhibitors: A Promising Wrench to Impair LSD1

Eupalinilide B as a novel anti-cancer agent that inhibits proliferation and epithelial–mesenchymal transition in laryngeal cancer cells

Therapeutic targeting of chromatin: status and opportunities

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