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TAK-418-418, a LSD1 inhibitor, can rescue the genome wide chromatin abnormality in hippocapmus tissue in KMT2D+/bGeo mice after 2 week treatment

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

ORGANISM(S): Mus musculus

PROVIDER: GSE146729 | GEO | 2020/03/11

REPOSITORIES: GEO

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TAK-418-418, a LSD1 inhibitor, can rescue the genome wide chromatin abnormality in hippocapmus tissue in KMT2D+/bGeo mice after 2 week treatment [RNA-seq]

Project description:Mutation in KMT2D, a histone-lysine N-methyl transferase, is responsible for majority of Kabuki syndrome in human. A mouse model of Kabuki syndrome with heterzygous mutation of KMT2D, KMT2D+/bGeo was created to understand the disease mechanism and for drug discovery. TAK-418-418, a lysine-specific histone demethylase (LSD1) inhibitor, was tested on these mice for therapeutic treatment of the disease. Differences between expression levels among different experimental conditions was evaluated by high throughput RNA sequencing (RNA-Seq).

2020-03-11 | GSE146728 | GEO

TAK-418-418, a LSD1 inhibitor, can rescue the genome wide chromatin abnormality in hippocapmus tissue in KMT2D+/bGeo mice after 2 week treatment [ChIP-seq]

Project description:KMT2D+/bGeoation in KMT2D, a histone-lysine N-methyl transferase, is responsible for majority of Kabuki syndrome in human. A mouse model of Kabuki syndrome with heterzygous KMT2D+/bGeoation of KMT2D, KMT2D+/bGeo was created to understand the disease mechanism and for drug discovery. TAK-418-418, a lysine-specific histone demethylase (LSD1) inhibitor, was tested on these mice for therapeutic treatment of the disease. Rescue of genome wide chromatin abnormality, which has been reported in KMT2D+/bGeo mice, was evaluated by high throughput next generation sequencing following chromatin immunoprecipitation of H3K4me1 and H3K4me3.

2020-03-11 | GSE146727 | GEO

TAK-418-418, a LSD1 inhibitor, can rescue the genome wide chromatin abnormality in hippocapmus tissue in KMT2D+/bGeo mice after 2 week treatment

Project description:TAK-418-418, a LSD1 inhibitor, can rescue the genome wide chromatin abnormality in hippocapmus tissue in KMT2D+/bGeo mice after 2 week treatment

| PRJNA611772 | ENA

TAK-418-418, a LSD1 inhibitor, can rescue the genome wide chromatin abnormality in hippocapmus tissue in KMT2D+/bGeo mice after 2 week treatment [RNA-seq]

Project description:TAK-418-418, a LSD1 inhibitor, can rescue the genome wide chromatin abnormality in hippocapmus tissue in KMT2D+/bGeo mice after 2 week treatment [RNA-seq]

| PRJNA611774 | ENA

TAK-418-418, a LSD1 inhibitor, can rescue the genome wide chromatin abnormality in hippocapmus tissue in KMT2D+/bGeo mice after 2 week treatment [ChIP-seq]

Project description:TAK-418-418, a LSD1 inhibitor, can rescue the genome wide chromatin abnormality in hippocapmus tissue in KMT2D+/bGeo mice after 2 week treatment [ChIP-seq]

| PRJNA611775 | ENA

LSD1 enzyme inhibitor TAK-418 unlocks aberrant epigenetic machinery and improves autism symptoms in neurodevelopmental disorder models.

Project description:Persistent epigenetic dysregulation may underlie the pathophysiology of neurodevelopmental disorders, such as autism spectrum disorder (ASD). Here, we show that the inhibition of lysine-specific demethylase 1 (LSD1) enzyme activity normalizes aberrant epigenetic control of gene expression in neurodevelopmental disorders. Maternal exposure to valproate or poly I:C caused sustained dysregulation of gene expression in the brain and ASD-like social and cognitive deficits after birth in rodents. Unexpectedly, a specific inhibitor of LSD1 enzyme activity, 5-((1R,2R)-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(tetrahydro-2H-pyran-4-yl)thiophene-3-carboxamide hydrochloride (TAK-418), almost completely normalized the dysregulated gene expression in the brain and ameliorated some ASD-like behaviors in these models. The genes modulated by TAK-418 were almost completely different across the models and their ages. These results suggest that LSD1 enzyme activity may stabilize the aberrant epigenetic machinery in neurodevelopmental disorders, and the inhibition of LSD1 enzyme activity may be the master key to recover gene expression homeostasis. TAK-418 may benefit patients with neurodevelopmental disorders.

| S-EPMC7954450 | biostudies-literature

Safety, pharmacokinetics and pharmacodynamics of TAK-418, a novel inhibitor of the epigenetic modulator lysine-specific demethylase 1A.

Project description:AimsDysregulation of histone methylation epigenetic marks may result in intellectual and developmental disability, as seen in Kabuki syndrome. Animal data suggest that increasing histone methylation by inhibiting lysine-specific demethylase 1A (LSD1) may improve cognitive outcomes in a model of Kabuki syndrome. TAK-418 is a novel LSD1 inhibitor, developed as a potential therapeutic agent for central nervous system disorders such as Kabuki syndrome. Here, we report safety, tolerability, pharmacokinetic and pharmacodynamic profiles of single and multiple doses of TAK-418 (ClinicalTrials.gov: NCT03228433, NCT03501069).MethodsTwo randomized, double-blind, placebo-controlled, phase 1 studies of oral TAK-418 were performed, a first-in-human single-rising-dose (SRD) study (5-60 mg) in healthy adult male and female volunteers (placebo, n = 10; TAK-418, n = 30), and an SRD (120-160 mg) and multiple-rising-dose (MRD) study (20-160 mg once daily for 10 days) in healthy female volunteers (placebo, n = 2 [SRD] and n = 6 [MRD]; TAK-418, n = 6 [SRD] and n = 18 [MRD]).ResultsTAK-418 was well tolerated. No clinically significant changes in laboratory test results or vital signs were observed and no serious adverse events were reported. TAK-418 had a nearly linear pharmacokinetic profile, with rapid absorption and short terminal half-life across the evaluated dose range. No obvious accumulation was observed after daily administration for 10 days. Administration with food delayed peak plasma concentrations but overall exposure was unaffected. TAK-418 rapidly crossed the blood-brain barrier and generally showed a dose-dependent response in the peripheral pharmacodynamic biomarker formyl-flavin adenine dinucleotide.ConclusionThe brain-penetrant LSD1 inhibitor TAK-418 was well tolerated, with pharmacokinetic and pharmacodynamic effects that support further investigation.

| S-EPMC9290503 | biostudies-literature

Animal models of neurodevelopmental disorders treated with TAK-418

Project description:This SuperSeries is composed of the SubSeries listed below.

2021-01-29 | GSE165676 | GEO

Novel dual LSD1/HDAC6 inhibitor for the treatment of cancer

Project description:Dually targeting the epigenetic proteins lysine specific demethylase 1 (LSD1) and histone deacetylases (HDACs) that play a key role in cancer cells by modulating gene repressor complexes including CoREST will have a profound effect in inhibiting tumour growth. Here, we evaluated JBI-097 a dual LSD1/HDAC6 inhibitor, for its in vitro and in vivo activities in various tumor models. In vitro, JBI-097 showed a strong potency in inhibiting LSD1 and HDAC6 enzymatic activities with the isoform selectivity over other HDACs. Cell-based experiments demonstrated a superior anti-proliferative profile against haematological and solid tumor cell lines. JBI-097 also showed strong modulation of HDAC6 and LSD1 specific biomarkers, alpha-tubulin, CD86, CD11b, and GFi1b. In vivo, JBI-097 showed a stronger effect in erythroleukemia, multiple myeloma xenograft models, and in CT-26 syngeneic model. JBI-097 also showed efficacy as monotherapy and additive or synergistic efficacy in combination with the standard of care or with immune checkpoint inhibitors. These and other findings suggest that JBI-097 could be a promising molecule for targeting the LSD1 and HDAC6. Further studies are warranted to elucidate the mechanism of action.

| S-EPMC9810167 | biostudies-literature

LET-418/Mi2 and SPR-5/LSD1 cooperatively prevent somatic reprogramming of C. elegans germline stem cells.

Project description:Throughout their journey to forming new individuals, germline stem cells must remain totipotent, particularly by maintaining a specific chromatin structure. However, the place epigenetic factors occupy in this process remains elusive. So far, "sensitization" of chromatin by modulation of histone arrangement and/or content was believed to facilitate transcription-factor-induced germ cell reprogramming. Here, we demonstrate that the combined reduction of two epigenetic factors suffices to reprogram C. elegans germ cells. The histone H3K4 demethylase SPR-5/LSD1 and the chromatin remodeler LET-418/Mi2 function together in an early process to maintain germ cell status and act as a barrier to block precocious differentiation. This epigenetic barrier is capable of limiting COMPASS-mediated H3K4 methylation, because elevated H3K4me3 levels correlate with germ cell reprogramming in spr-5; let-418 mutants. Interestingly, germ cells deficient for spr-5 and let-418 mainly reprogram as neurons, suggesting that neuronal fate might be the first to be derepressed in early embryogenesis.

| S-EPMC3986580 | biostudies-literature

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