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Inhibitors of the histone lysine demethylase KDM1A are broadly efficacious in AML by evicting the enzyme from chromatin

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE71741 | GEO | 2016/02/10

SECONDARY ACCESSION(S): PRJNA291975

REPOSITORIES: GEO

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Inhibitors of the histone lysine demethylase KDM1A are broadly efficacious in AML by evicting the enzyme from chromatin

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2016-02-10 | E-GEOD-71741 | biostudies-arrayexpress

Inhibitors of the histone lysine demethylase KDM1A are broadly efficacious in AML by evicting the enzyme from chromatin [RNA-Seq]

Project description:Investigating the effects of two different classes of KDM1A inhibitors on the transcriptome of AML cell lines 16 different samples with biological replicates. Treatment for 24 and 72 hours with an irreversible KDM1A inhibitor (RN-1) or a reversible KDM1A inhibitor (GSK690) or an inactive isomer of the latter (GSK690*).

2016-02-10 | E-GEOD-71740 | biostudies-arrayexpress

Inhibitors of the histone lysine demethylase KDM1A are broadly efficacious in AML by evicting the enzyme from chromatin [ChIP-Seq]

Project description:Examine the distribution of KDM1A and the histone H3K4me2 mark on chromatin following treatment with two distinct classes of KDM1A inhibitors - an irreversible inhibitor (RN-1) and a reversible inhibitor (GSK690) 15 samples total from two treated cell lines - 9 from Kasumi-1 and 6 from SKNO-1. Controls included were input DNA isolated from the treated cells.

2016-02-10 | E-GEOD-71739 | biostudies-arrayexpress

Inhibitors of the histone lysine demethylase KDM1A are broadly efficacious in AML by evicting the enzyme from chromatin [RNA-Seq]

Project description:Investigating the effects of two different classes of KDM1A inhibitors on the transcriptome of AML cell lines

2016-02-10 | GSE71740 | GEO

Inhibitors of the histone lysine demethylase KDM1A are broadly efficacious in AML by evicting the enzyme from chromatin [ChIP-Seq]

2016-02-10 | GSE71739 | GEO

Histone Lysine Demethylase Inhibitors.

Project description:The dynamic regulation of covalent modifications to histones is essential for maintaining genomic integrity and cell identity and is often compromised in cancer. Aberrant expression of histone lysine demethylases has been documented in many types of blood and solid tumors, and thus demethylases represent promising therapeutic targets. Recent advances in high-throughput chemical screening, structure-based drug design, and structure-activity relationship studies have improved both the specificity and the in vivo efficacy of demethylase inhibitors. This review will briefly outline the connection between demethylases and cancer and will provide a comprehensive overview of the structure, specificity, and utility of currently available demethylase inhibitors. To date, a select group of demethylase inhibitors is being evaluated in clinical trials, and additional compounds may soon follow from the bench to the bedside.

| S-EPMC5204329 | biostudies-other

Histone lysine specific demethylase 1 inhibitors.

Project description:LSD1 plays a pivotal role in numerous biological functions. The overexpression of LSD1 is reported to be associated with different malignancies. Over the last decade, LSD1 has emerged as an interesting target for the treatment of acute myeloid leukaemia (AML). Numerous researchers have designed, synthesized, and evaluated various LSD1 inhibitors with diverse chemical architectures. Some of these inhibitors have entered clinical trials and are currently at different phases of clinical evaluation. This comprehensive review enlists recent research developments in LSD1 targeting pharmacophores reported over the last few years.

| S-EPMC7513387 | biostudies-literature

Activity-dependent Regulation of Histone Lysine Demethylase KDM1A by a Putative Thiol/Disulfide Switch.

Project description:Lysine demethylation of proteins such as histones is catalyzed by several classes of enzymes, including the FAD-dependent amine oxidases KDM1A/B. The KDM1 family is homologous to the mitochondrial monoamine oxidases MAO-A/B and produces hydrogen peroxide in the nucleus as a byproduct of demethylation. Here, we show KDM1A is highly thiol-reactive in vitro and in cellular models. Enzyme activity is potently and reversibly inhibited by the drug disulfiram and by hydrogen peroxide. Hydrogen peroxide produced by KDM1A catalysis reduces thiol labeling and inactivates demethylase activity over time. MALDI-TOF mass spectrometry indicates that hydrogen peroxide blocks labeling of cysteine 600, which we propose forms an intramolecular disulfide with cysteine 618 to negatively regulate the catalytic activity of KDM1A. This activity-dependent regulation is unique among histone-modifying enzymes but consistent with redox sensitivity of epigenetic regulators.

| S-EPMC5114423 | biostudies-literature

Development of the triazole-fused pyrimidine derivatives as highly potent and reversible inhibitors of histone lysine specific demethylase 1 (LSD1/KDM1A).

Project description:Histone lysine specific demethylase 1 (LSD1) has been recognized as an important modulator in post-translational process in epigenetics. Dysregulation of LSD1 has been implicated in the development of various cancers. Herein, we report the discovery of the hit compound 8a (IC50 = 3.93 μmol/L) and further medicinal chemistry efforts, leading to the generation of compound 15u (IC50 = 49 nmol/L, and K i = 16 nmol/L), which inhibited LSD1 reversibly and competitively with H3K4me2, and was selective to LSD1 over MAO-A/B. Docking studies were performed to rationalize the potency of compound 15u. Compound 15u also showed strong antiproliferative activity against four leukemia cell lines (OCL-AML3, K562, THP-1 and U937) as well as the lymphoma cell line Raji with the IC50 values of 1.79, 1.30, 0.45, 1.22 and 1.40 μmol/L, respectively. In THP-1 cell line, 15u significantly inhibited colony formation and caused remarkable morphological changes. Compound 15u induced expression of CD86 and CD11b in THP-1 cells, confirming its cellular activity and ability of inducing differentiation. The findings further indicate that targeting LSD1 is a promising strategy for AML treatment, the triazole-fused pyrimidine derivatives are new scaffolds for the development of LSD1/KDM1A inhibitors.

| S-EPMC6663923 | biostudies-literature

Chemoprobe-based assays of histone lysine demethylase 1A target occupation enable <i>in vivo</i> pharmacokinetics and pharmacodynamics studies of KDM1A inhibitors.

Project description:Screening of cellular activity for inhibitors of histone lysine modifiers is most frequently performed indirectly by analyzing changes in the total levels of histone marks targeted by lysine methylases/demethylases. However, inhibition of histone lysine modifiers often leads to local rather than total changes in histone marks. Also, because histone modifications can be modulated by more than one cellular enzyme, it is not always clear whether changes in histone marks are a direct or indirect consequence of the inhibitor treatment applied. Direct assessment of target occupation can provide a useful tool to quantify the fraction of an epigenetic modifier that is bound to a pharmacological inhibitor (target engagement). Here, we developed and used a novel chemoprobe-based immunoassay to quantify target engagement in cells. Quantification of the fraction of free KDM1A was made possible, in an immune-based assay, by coupling a biotinylated chemoprobe to a warhead capable of selectively and irreversibly binding to the free active form of KDM1A. The results obtained confirmed that this approach is able to determine the degree of target engagement in a dose-dependent manner. Furthermore, the assay can be also used on tissue extracts to analyze the in vivo pharmacokinetics and pharmacodynamics relationship of KDM1A inhibitors, as has been exemplified with ORY-1001 (iadademstat), a potent and irreversible inhibitor of KDM1A. The principle of this assay may be applied to other targets, and the KDM1A probe may be employed in chemoproteomic analyses.

| S-EPMC6527171 | biostudies-literature

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