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

Liu, Hong‐Min; Suo, Feng-Zhi; Li, Xiaobo; You, Yinghua; Lv, Chun-Tao; Zheng, Chen-Xing; Zhang, Guochen; Liu, Yue-Jiao; Kang, Wen-Ting; Zheng, Yi-Chao; Xu, Haiwei

doi:10.1016/j.ejmech.2019.04.065

Cited by 29 publications

(11 citation statements)

References 31 publications

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“…It has been shown to be overexpressed in diverse cancers and contributes to cancer development and progress as an oncogene, thus, inhibition of KDM1A pharmacologically can suppress the proliferation and migration of diverse cancer cells (Zheng et al, 2015;Zheng et al, 2016c;Dai et al, 2020;Jia et al, 2020). Until now, there are plenty of articles that concerning the discovery and development of KDM1A inhibitors (Zheng et al, 2016b;Sun et al, 2017;Xi et al, 2017;Duan et al, 2018;Xi et al, 2018;Xu et al, 2018;Li Z.-R. et al, 2019;Liu et al, 2019), nevertheless, only several of them have entered into clinical trials (Zheng et al, 2015;Zheng et al, 2016;Dai et al, 2020). Thereby, discovery of KDM1A inhibitor with new skeleton is in needed.…”

Section: Introductionmentioning

confidence: 99%

Monobenzone, a Novel and Potent KDM1A Inhibitor, Suppresses Migration of Gastric Cancer Cells

Jia

Song

2021

Front. Pharmacol.

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Lysine-specific demethylase1 (KDM1A) is generally highly expressed in various cancer tissues, and promotes the initiation and development of cancers via diverse cellular signaling pathways. Therefore, KDM1A is a promising drug target in many cancers, and it is crucial to find effective KDM1A inhibitors, while none of them has entered into market. With the help of compound library, monobenzone, a local depigmentor using as a treating over-pigmentation in clinic, was characterized as an effective KDM1A inhibitor (IC50 = 0.4507 μM), which may competitively inhibit KDM1A reversibly. Further cellular study confirmed that monobenzone could inhibit the proliferation of gastric cancer cell lines MGC-803 and BGC-823 with IC50 as 7.82 ± 0.55 μM and 6.99 ± 0.51 μM, respectively, and erase the substrate of KDM1A, H3K4me1/2 and H3K9 me2, and inhibit the migration of gastric cancer cell by reversing epithelial–mesenchymal transition (EMT). As the structure of monobenzone is very simple and small, this study provides a novel backbone for the further optimization of KDM1A inhibitor and gives monobenzone potential new application.

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Section: Introductionmentioning

confidence: 99%

Monobenzone, a Novel and Potent KDM1A Inhibitor, Suppresses Migration of Gastric Cancer Cells

Jia

Song

2021

Front. Pharmacol.

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“…As the cofactor of LSD1 is FAD 41 , 42 , compounds with similar structure to FAD may compete with FAD for binding to LSD1, which may represent a promising approach to inhibit the activity of LSD1. In previous work, we have reported several new LSD1 inhibitors 8 , 29 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , among which 1,2,3-triazole-dithiocarbamate hybrids exhibited moderate inhibitory activity by competitively binding to LSD1. In an effort to design and develop novel and potent LSD1 inhibitors, we screened our in-house pyrimidine derivatives on LSD1 inhibitory activity.…”

Section: Introductionmentioning

confidence: 99%

Exploration of 5-cyano-6-phenylpyrimidin derivatives containing an 1,2,3-triazole moiety as potent FAD-based LSD1 inhibitors

Wang

You

et al. 2020

Acta Pharmaceutica Sinica B

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Histone lysine specific demethylase 1 (LSD1) has become a potential therapeutic target for the treatment of cancer. Discovery and develop novel and potent LSD1 inhibitors is a challenge, although several of them have already entered into clinical trials. Herein, for the first time, we reported the discovery of a series of 5-cyano-6-phenylpyrimidine derivatives as LSD1 inhibitors using flavin adenine dinucleotide (FAD) similarity-based designing strategy, of which compound 14q was finally identified to repress LSD1 with IC 50 = 183 nmol/L. Docking analysis suggested that compound 14q fitted well into the FAD-binding pocket. Further mechanism studies showed that compound 14q may inhibit LSD1 activity competitively by occupying the FAD binding sites of LSD1 and inhibit cell migration and invasion by reversing epithelial to mesenchymal transition (EMT). Overall, these findings showed that compound 14q is a suitable candidate for further development of novel FAD similarity-based LSD1 inhibitors.

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“…In the past decades, numerous LSD1 inhibitors were developed and could be divided into irreversible and reversible types according to their action mechanisms. [14][15][16][17][18][19][20][21][22][23][24][25] Currently, irreversible LSD1 inhibitors based on tranylcypromine (TCP) scaffolding have achieved good progress, illustrated by the two most advanced drug candidates ORY-1001 and GSK2879552 (Figure 1A). [26,27] Their inhibition mechanism involves the formation of an amine cation radical to covalently react with FAD to block the biological function of LSD1 (Figure 1B).…”

Section: Introductionmentioning

confidence: 99%

New tranylcypromine derivatives containing sulfonamide motif as potent LSD1 inhibitors to target acute myeloid leukemia: Design, synthesis and biological evaluation

Liang

Wang

et al. 2020

Bioorganic Chemistry

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

Cited by 29 publications

References 31 publications

Monobenzone, a Novel and Potent KDM1A Inhibitor, Suppresses Migration of Gastric Cancer Cells

Monobenzone, a Novel and Potent KDM1A Inhibitor, Suppresses Migration of Gastric Cancer Cells

Exploration of 5-cyano-6-phenylpyrimidin derivatives containing an 1,2,3-triazole moiety as potent FAD-based LSD1 inhibitors

New tranylcypromine derivatives containing sulfonamide motif as potent LSD1 inhibitors to target acute myeloid leukemia: Design, synthesis and biological evaluation

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