Annual review of lysine-specific demethylase 1 (LSD1/KDM1A) inhibitors in 2021

Song, Yihui; Zhang, Huiqing; Yang, Xiaoke; Yalong, Shi; Yu, Bin

doi:10.1016/j.ejmech.2021.114042

Cited by 41 publications

(25 citation statements)

References 47 publications

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“… 327 And the current status of its clinical inhibitor development is reviewed in Ref. 328 The LSD1 inhibitor chalcone (a,b‐unsaturated aromatic ketone) has clinical potential against a variety of diseases due to its broad pharmacological activities, including antioxidant, antiulcer, antiviral, anticancer, antibacterial, antiangiogenic, and anti‐inflammatory activities. 329 T‐448 induces LSD1 demethylase activity in the brain, and improve learning ability in mice with little hematologic toxicity, suggesting that it may be a promising treatment for neurodevelopmental disorders 296 (Table 1 ).…”

Section: Epigenetic‐targeted Therapy For Inflammation‐related Diseasesmentioning

confidence: 99%

Targeting epigenetic regulators for inflammation: Mechanisms and intervention therapy

Zhang

Meng

Zhou

et al. 2022

MedComm

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Emerging evidence indicates that resolution of inflammation is a critical and dynamic endogenous process for host tissues defending against external invasive pathogens or internal tissue injury. It has long been known that autoimmune diseases and chronic inflammatory disorders are characterized by dysregulated immune responses, leading to excessive and uncontrol tissue inflammation. The dysregulation of epigenetic alterations including DNA methylation, posttranslational modifications to histone proteins, and noncoding RNA expression has been implicated in a host of inflammatory disorders and the immune system. The inflammatory response is considered as a critical trigger of epigenetic alterations that in turn intercede inflammatory actions. Thus, understanding the molecular mechanism that dictates the outcome of targeting epigenetic regulators for inflammatory disease is required for inflammation resolution. In this article, we elucidate the critical role of the nuclear factor‐κB signaling pathway, JAK/STAT signaling pathway, and the NLRP3 inflammasome in chronic inflammatory diseases. And we formulate the relationship between inflammation, coronavirus disease 2019, and human cancers. Additionally, we review the mechanism of epigenetic modifications involved in inflammation and innate immune cells. All that matters is that we propose and discuss the rejuvenation potential of interventions that target epigenetic regulators and regulatory mechanisms for chronic inflammation‐associated diseases to improve therapeutic outcomes.

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Section: Epigenetic‐targeted Therapy For Inflammation‐related Diseasesmentioning

confidence: 99%

Targeting epigenetic regulators for inflammation: Mechanisms and intervention therapy

Zhang

Meng

Zhou

et al. 2022

MedComm

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“…LSD1 plays heterogeneous roles via transcriptionally modulating its downstream genes in demethylase-dependent or -independent modes in varieties of cancers (Song et al, 2022; Yang Frontiers in Pharmacology frontiersin.org et al, 2022). It acts as an oncogene in some cancers, while functioning as a cancer-suppressor gene in the other cancers (Yang et al, 2018a;Hu et al, 2019).…”

Section: The Functions and Regulations Of Lsd1mentioning

confidence: 99%

“…Natural products are one of the major sources in drug discovery due to their diverse chemical scaffolds and activity profiles (Fang et al, 2020;Yang et al, 2020;Yang et al, 2021a;Cheng et al, 2022b;Song et al, 2022). Many natural products and their derivatives have been found with in vitro inhibitory activity against LSD1.…”

Section: Natural Productsmentioning

confidence: 99%

“…Lysine-specific demethylase 1 (LSD1) is a flavin-dependent lysine-specific histone demethylase first identified in 2004 and mediated transcriptional activation or repression via erasing methyl groups from H3K9me2/1 and H3K4me2/1, respectively (Figure 1) (Shi et al, 2004;Fang et al, 2020;Kim et al, 2021;Malagraba et al, 2022;Song et al, 2022). Recently studies found that LSD1 could also remove the methyl groups from several non-histone proteins such as ERα, MTA1, HIF-1α, AGO2, HSP90, MEFD2, and STAT3 and be involved in many cancer cell events (Majello et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

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A state-of-the-art review on LSD1 and its inhibitors in breast cancer: Molecular mechanisms and therapeutic significance

et al. 2022

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Breast cancer (BC) is a kind of malignant cancer in women, and it has become the most diagnosed cancer worldwide since 2020. Histone methylation is a common biological epigenetic modification mediating varieties of physiological and pathological processes. Lysine-specific demethylase 1 (LSD1), a first identified histone demethylase, mediates the removal of methyl groups from histones H3K4me1/2 and H3K9me1/2 and plays a crucial role in varieties of cancer progression. It is also specifically amplified in breast cancer and contributes to BC tumorigenesis and drug resistance via both demethylase and non-demethylase manners. This review will provide insight into the overview structure of LSD1, summarize its action mechanisms in BC, describe the therapeutic potential of LSD1 inhibitors in BC, and prospect the current opportunities and challenges of targeting LSD1 for BC therapy.

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“…Abnormal overexpression of LSD1 was found in a variety of solid tumors, including neuroblastoma, breast, prostate, bladder, lung, liver, and colorectal tumors (Kahl et al, 2006;Lim et al, 2010;Hayami et al, 2011;Harris et al, 2012;Zhao et al, 2012;Sorna et al, 2013), where it inhibits differentiation, and enhances proliferation, invasiveness, and cell motility, and also worsens prognosis (Schenk et al, 2012;Luka et al, 2014). Recent studies have unequivocally demonstrated that blocking LSD1 demethylase activity using LSD1 inhibitors significantly slowed the spread of cancer cells (Fu et al, 2021;Dong et al, 2022;Song et al, 2022). Therefore, considerable interest emerged in the LSD1 inhibition as potential anti-cancer therapeutic strategy.…”

Section: Anti-proliferative Effect Of Potential Lsd1/corest Inhibitor...mentioning

confidence: 99%

Anti-Proliferative Effect of Potential LSD1/CoREST Inhibitors Based on Molecular Dynamics Model for Treatment of SH-SY5Y Neuroblastoma Cancer Cell Line

Zalloum

Zalloum²,

Hameduh³

et al. 2022

Asian Pac J Cancer Prev

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Background: Lysine-specific demethylase is a demethylase enzyme that can remove methyl groups from histones H3K4me1/2 and H3K9me1/2. It is expressed in many cancers, where it impedes differentiation and contributes to cancer cell proliferation, cell metastasis and invasiveness, and is associated with inferior prognosis. LSD1 is associated with its corepressor protein CoREST, and utilizes tetrahydrofolate as a cofactor to accept CH 2 from the demethylation process. The fact that the cofactor is best bound to the active site inspired us to explore its interactions to LSD1/CoREST enzyme complex utilizing molecular dynamics simulation, which aids designing novel and potent inhibitors. Objective: In this study we minted to identify a new potential LSD1/CoREST inhibitors and test the potency and the safety of such inhibitors against human neuroblastoma and fibroblast cells lines. Methods: We have implemented a previously derived model from the molecular dynamics simulation study and the key contacts to the active site in a subsequent structure based drug design and in-silico screening, which revealed a number of potential inhibitors toward LSD1/CoREST complex. The anti-proliferative activities of the identified compounds will be tested against neuroblastoma SH-SY5Y cancer cell line which known to highly express LSD1/CoREST complex. Results: In-silico mining on National Cancer Institute (NCI) database identified 55 promising and structurally diverse inhibitors. Applying the abovementioned molecular modeling procedure yielded four compounds of LSD1/CoREST inhibiters with IC 50 < 2µM. The four lead compounds were tested against SH-SY5Y neuroblastoma cell line that known to express high level of LSD1 and illustrated a potent activity with an IC 50 ranging from 0.195 to 1.52µM. To estimate the toxicity of the selective leads, they were tested against normal fibroblast cells and scored a relatively high IC 50 ranging from 0.303 to ≥ 100µM. Conclusion: Our model revealed promising inhibitors that can be used in treating cancers that overexpress the LSD1 enzyme such as the SH-SY5Y neuroblastoma.

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Annual review of lysine-specific demethylase 1 (LSD1/KDM1A) inhibitors in 2021

Cited by 41 publications

References 47 publications

Targeting epigenetic regulators for inflammation: Mechanisms and intervention therapy

Targeting epigenetic regulators for inflammation: Mechanisms and intervention therapy

A state-of-the-art review on LSD1 and its inhibitors in breast cancer: Molecular mechanisms and therapeutic significance

Anti-Proliferative Effect of Potential LSD1/CoREST Inhibitors Based on Molecular Dynamics Model for Treatment of SH-SY5Y Neuroblastoma Cancer Cell Line

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