212 Novel anti-tumor activity of targeted LSD1 inhibition by GSK2879552

Mohammad, Hojouj; Smitheman, Kimberly N.; Aller, Glenn Van; Cusan, Martina; Kamat, Shrivallabh P.; Liu, Y.; Johnson, Nancy; Hann, Christine L.; Armstrong, Scott A.; Krüger, Ralf

doi:10.1016/s0959-8049(14)70338-7

Cited by 20 publications

(11 citation statements)

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“…Concurrently, GlaxoSmithKline developed a potent, selective and mechanism-based irreversible LSD1 inhibitor, GSK2879552. Similar to ORY-1001, GSK2879552 is able to promote the differentiation of AML cells and inhibit the growth of SCLC and AML cells, and an extended survival is also observed in a mouse model after administration of this drug in vivo (Trial Numbers NCT02177812 and NCT02034123) (Mohammad et al, 2014). Thus, tranylcypromine derivatives demonstrate the potential to become novel epigenetic anticancer drugs.…”

Section: Lsd1/2: Mono-and Di-methyl Lysine Histone Demethylasesmentioning

confidence: 96%

“…Recently, two tranylcypromine derivatives, ORY-1001 and GSK2879552, are in clinical trials for patients with AML and/or small cell lung cancers (SCLC) (Rhyasen, 2015;Finley & Copeland, 2014;Mohammad et al, 2014) (Table 1). ORY-1001 is in phase I clinical trials by Oryzon, a private European-based biotech company (Trial Number 2013-002447-29).…”

Section: Lsd1/2: Mono-and Di-methyl Lysine Histone Demethylasesmentioning

confidence: 99%

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Epigenetic targets and drug discovery Part 2: Histone demethylation and DNA methylation

Liu

Lau

et al. 2015

Pharmacology & Therapeutics

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Section: Lsd1/2: Mono-and Di-methyl Lysine Histone Demethylasesmentioning

confidence: 96%

Section: Lsd1/2: Mono-and Di-methyl Lysine Histone Demethylasesmentioning

confidence: 99%

Epigenetic targets and drug discovery Part 2: Histone demethylation and DNA methylation

Liu

Lau

et al. 2015

Pharmacology & Therapeutics

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“…[154][155][156] Meanwhile, GSK also disclosed N-substituted tranylcypromine derivatives as LSD1 inhibitors, and now, one of them has entered clinical trial either. 157,158 Different from the previously reported 2-PCPA-based LSD1 inhibitors, Mattevi et al reported one group of 1-substituted cyclopropylamine derivatives as LSD1 inhibitors; the most powerful one, compound 13, performed strong LSD1 inhibitory effect with IC 50 of 0.131 μmol/L, which gives a new insight for the 2-PCPA-based LSD1 inhibitor modification. 159 Similarly, Costantino also claimed a new group of 1-substituted 2-PCPA derivatives; compound 14 performed nanomolar range inhibitory effect against LSD1 with IC 50 of 0.031 μmol/L.…”

Section: A Trans-2-phenylcyclopropylamine and Its Derivativesmentioning

confidence: 95%

“…This compound is currently undergoing phase II clinical trial for acute myelogenous leukemia treatment . Meanwhile, GSK also disclosed N ‐substituted tranylcypromine derivatives as LSD1 inhibitors, and now, one of them has entered clinical trial either . Different from the previously reported 2‐PCPA ‐based LSD1 inhibitors, Mattevi et al.…”

Section: Lsd1 Inhibitorsmentioning

confidence: 99%

A Systematic Review of Histone Lysine‐Specific Demethylase 1 and Its Inhibitors

Zheng¹,

Wang²,

Li³

et al. 2015

Medicinal Research Reviews

161

130

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Histone lysine-specific demethylase 1 (LSD1) is the first discovered and reported histone demethylase by Dr. Shi Yang's group in 2004. It is classified as a member of amine oxidase superfamily, the common feature of which is using the flavin adenine dinucleotide (FAD) as its cofactor. Since it is located in cell nucleus and acts as a histone methylation eraser, LSD1 specifically removes mono- or dimethylated histone H3 lysine 4 (H3K4) and H3 lysine 9 (H3K9) through formaldehyde-generating oxidation. It has been indicated that LSD1 and its downstream targets are involved in a wide range of biological courses, including embryonic development and tumor-cell growth and metastasis. LSD1 has been reported to be overexpressed in variety of tumors. Inactivating LSD1 or downregulating its expression inhibits cancer-cell development. LSD1 targeting inhibitors may represent a new insight in anticancer drug discovery. This review summarizes recent studies about LSD1 and mainly focuses on the basic physiological function of LSD1 and its involved mechanisms in pathophysiologic conditions, as well as the development of LSD1 inhibitors as potential anticancer therapeutic agents.

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“…Unfortunately, these inhibitors had no significant inhibitory effect on LSD1 and poor selectivity [17]. However, by optimizing the structure of these compounds, LSD1 inhibitors with high activity have been designed, such as ORY-1001, as seen in Figure 1D [18], and GSK2879552, as seen in Figure 1E [19], which are both TCPA derivatives. At present, they have entered clinical research and have shown good inhibition of LSD1: IC 50 = 18 nM and IC 50 = 20 nM, respectively.…”

Section: Introductionmentioning

confidence: 99%

Investigating the Binding Mode of Reversible LSD1 Inhibitors Derived from Stilbene Derivatives by 3D-QSAR, Molecular Docking, and Molecular Dynamics Simulation

Yang

et al. 2019

Molecules

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Overexpression of lysine specific demethylase 1 (LSD1) has been found in many cancers. New anticancer drugs targeting LSD1 have been designed. The research on irreversible LSD1 inhibitors has entered the clinical stage, while the research on reversible LSD1 inhibitors has progressed slowly so far. In this study, 41 stilbene derivatives were studied as reversible inhibitors by three-dimensional quantitative structure–activity relationship (3D-QSAR). Comparative molecular field analysis (CoMFA q 2 = 0.623, r 2 = 0.987, r pred 2 = 0.857) and comparative molecular similarity indices analysis (CoMSIA q 2 = 0.728, r 2 = 0.960, r pred 2 = 0.899) were used to establish the model, and the structure–activity relationship of the compounds was explained by the contour maps. The binding site was predicted by two different kinds of software, and the binding modes of the compounds were further explored. A series of key amino acids Val288, Ser289, Gly314, Thr624, Lys661 were found to play a key role in the activity of the compounds. Molecular dynamics (MD) simulations were carried out for compounds 04, 17, 21, and 35, which had different activities. The reasons for the activity differences were explained by the interaction between compounds and LSD1. The binding free energy was calculated by molecular mechanics generalized Born surface area (MM/GBSA). We hope that this research will provide valuable information for the design of new reversible LSD1 inhibitors in the future.

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212 Novel anti-tumor activity of targeted LSD1 inhibition by GSK2879552

Cited by 20 publications

References 0 publications

Epigenetic targets and drug discovery Part 2: Histone demethylation and DNA methylation

Epigenetic targets and drug discovery Part 2: Histone demethylation and DNA methylation

A Systematic Review of Histone Lysine‐Specific Demethylase 1 and Its Inhibitors

Investigating the Binding Mode of Reversible LSD1 Inhibitors Derived from Stilbene Derivatives by 3D-QSAR, Molecular Docking, and Molecular Dynamics Simulation

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