Drug discovery of histone lysine demethylases (KDMs) inhibitors (progress from 2018 to present)

He, Xingrui; Zhang, Hang; Zhang, Y; Yang, Yong; Wang, Shuo; Bai, Renren; Xie, Tian; Ye, Xiang‐Yang

doi:10.1016/j.ejmech.2022.114143

Cited by 11 publications

(10 citation statements)

References 141 publications

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“…Due to the potential of LSD1 as an anti-cancer target, several LSD1 inhibitors have been explored, and the majority of the very powerful LSD1 inhibitors have only recently been found [43, 44]. Peptides, trans-2-phenylcyclopropylamine derivatives, polyamines, and guanidine are among the inhibitors [45].…”

Section: Discussionmentioning

confidence: 99%

Anti-proliferative effect of potential LSD1/CoREST inhibitors based on molecular dynamics model for treatment of SH-SY5Y neuroblastoma cancer cell line

Zalloum¹,

Zalloum

Hameduh³

et al. 2022

Preprint

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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 is associated with inferior prognosis. LSD1 is associated with its corepressor protein CoREST, and utilizes tetrahydrofolate as a cofactor to accept CH2 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. We have implemented a previously derived model from the MD simulation study and the key contacts to the active site in a subsequent structure based drug design and in-silico screening. In silico mining on National Cancer Institute (NCI) database identified 55 promising and structurally diverse inhibitors toward LSD1/CoREST complex. The anti-proliferative activities of the identified compounds were tested against neuroblastoma SH-SY5Y cancer cell line which known to highly express LSD1/CoREST complex. Applying the abovementioned molecular modeling procedure yielded Four compounds of LSD1/CoREST inhibiters with IC50 <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 IC50 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 IC50 ranging from 0.303 to ≥100µM. These compounds are excellent candidates treating cancers that overexpress the LSD1 enzyme.

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Section: Discussionmentioning

confidence: 99%

Anti-proliferative effect of potential LSD1/CoREST inhibitors based on molecular dynamics model for treatment of SH-SY5Y neuroblastoma cancer cell line

Zalloum¹,

Zalloum

Hameduh³

et al. 2022

Preprint

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show abstract

“…Due to the potential of LSD1 as an anti-cancer target, several LSD1 inhibitors have been explored, and the majority of the very powerful LSD1 inhibitors have only recently been found (Fu et al, 2017;He et al, 2022). Peptides, trans-2-phenylcyclopropylamine derivatives, polyamines, and guanidine are among the inhibitors (Stazi et al, 2016).…”

Section: Discussionmentioning

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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“…Although many inhibitors of this family of demethylases are reported, the majority of them are 2-OG competitors that coordinate with Fe 2+ ions in the catalytic center and sometimes compete with the histone substrate(s). However, most of these inhibitors are not specific only to the JmjC domain–containing demethylase, and the mechanisms of actions in cellular studies are poorly defined [ 56 , 57 ]. Moreover, the genome-wide effects of most of the inhibitors on methylated histones and in vivo specificities remain largely unclarified.…”

Section: Inhibitors Of Jmjc Domain–containing Lysine Demethylasesmentioning

confidence: 99%

Chemical Inhibitors Targeting the Histone Lysine Demethylase Families with Potential for Drug Discovery

2023

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The dynamic regulation of histone methylation and demethylation plays an important role in the regulation of gene expression. Aberrant expression of histone lysine demethylases has been implicated in various diseases including intractable cancers, and thus lysine demethylases serve as promising therapeutic targets. Recent studies in epigenomics and chemical biology have led to the development of a series of small-molecule demethylase inhibitors that are potent, specific, and have in vivo efficacy. In this review, we highlight emerging small-molecule inhibitors targeting the histone lysine demethylases and their progress toward drug discovery.

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Drug discovery of histone lysine demethylases (KDMs) inhibitors (progress from 2018 to present)

Cited by 11 publications

References 141 publications

Anti-proliferative effect of potential LSD1/CoREST inhibitors based on molecular dynamics model for treatment of SH-SY5Y neuroblastoma cancer cell line

Anti-proliferative effect of potential LSD1/CoREST inhibitors based on molecular dynamics model for treatment of SH-SY5Y neuroblastoma cancer cell line

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

Chemical Inhibitors Targeting the Histone Lysine Demethylase Families with Potential for Drug Discovery

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