TAK-418
目录号 : GC63437TAK-418 是一种选择性的,具有口服活性的 LSD1 (KDM1A) 酶抑制剂,IC50 为 2.9 nM。TAK-418 在神经发育障碍模型中解除异常的表观遗传机制并改善孤独症症状。
Cas No.:1818252-53-7
Sample solution is provided at 25 µL, 10mM.
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TAK-418 is a selective, orally active LSD1 (KDM1A) enzyme inhibitor with an IC50 of 2.9 nM. TAK-418 unlocks aberrant epigenetic machinery and improves autism symptoms in neurodevelopmental disorder models[1][2].
TAK-418 (1 mg/kg; p.o.; once daily for 14 days) ameliorates some autism spectrum disorder (ASD) -like behaviors in neurodevelopmental disorder model rodents[1].TAK-418 increases H3K4me1/2/3 and H3K9me2 levels at the Ucp2 gene and induced Ucp2 mRNA expression in primary cultured rat neurons. TAK-418 also increases H3K4me1/2/3 at the Bdnf gene. TAK-418 avoids the steric interference with GFI1B in the binding pocket through the generation of a compact formylated adduct form of coenzyme flavin adenine dinucleotide (FAD). TAK-418 shows a good pharmacokinetic profile in rodents and inhibits LSD1 enzyme activity in the brain without causing hematological toxicity in rodents[1].Single administration of TAK-418 at 1 or 3 mg/kg increases H3K4me2 levels at Ucp2 gene in the mouse brain[1]. TAK-418 can ameliorate neurological problems at the cellular, molecular, gene expression, and functional levels in a mouse model of KS (Kmt2d+/βGeo mice)[2].
[1]. Baba R, et al. LSD1 enzyme inhibitor TAK-418 unlocks aberrant epigenetic machinery and improves autism symptoms in neurodevelopmental disorder models. Sci Adv. 2021;7(11):eaba1187. Published 2021 Mar 12.
[2]. Zhang L, et al. Inhibition of KDM1A activity restores adult neurogenesis and improves hippocampal memory in a mouse model of Kabuki syndrome. Mol Ther Methods Clin Dev. 2021;20:779-791. Published 2021 Feb 18
Cas No. | 1818252-53-7 | SDF | |
分子式 | C17H25ClN2O2S | 分子量 | 356.91 |
溶解度 | 储存条件 | Store at -20°C, sealed storage, away from moisture and light | |
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Safety, pharmacokinetics and pharmacodynamics of TAK-418, a novel inhibitor of the epigenetic modulator lysine-specific demethylase 1A
Br J Clin Pharmacol 2021 Dec;87(12):4756-4768.PMID:33990969DOI:10.1111/bcp.14912.
Aims: Dysregulation 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). Methods: Two 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]). Results: TAK-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. Conclusion: The brain-penetrant LSD1 inhibitor TAK-418 was well tolerated, with pharmacokinetic and pharmacodynamic effects that support further investigation.
LSD1 enzyme inhibitor TAK-418 unlocks aberrant epigenetic machinery and improves autism symptoms in neurodevelopmental disorder models
Sci Adv 2021 Mar 12;7(11):eaba1187.PMID:33712455DOI:10.1126/sciadv.aba1187.
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.
Investigating the Therapeutic Potential of LSD1 Enzyme Activity-Specific Inhibition by TAK-418 for Social and Memory Deficits in Rodent Disease Models
ACS Chem Neurosci 2022 Feb 2;13(3):313-321.PMID:35061371DOI:10.1021/acschemneuro.1c00713.
Inhibition of lysine-specific demethylase 1 (LSD1) enzyme activity is a promising approach to treat diseases associated with epigenetic dysregulation, such as neurodevelopmental disorders. However, this concept has not been fully validated because genetic LSD1 deletion causes embryonic lethality and conventional LSD1 inhibitors cause thrombocytopenia via the dissociation of LSD1-cofactor complex. To characterize the therapeutic potential of LSD1 enzyme inhibition, we used TAK-418 and T-448, the LSD1 enzyme activity-specific inhibitors with minimal impact on the LSD1-cofactor complex. TAK-418 and T-448, by inhibiting brain LSD1 enzyme activity, consistently improved social deficits in animal models of neurodevelopmental disorders without causing thrombocytopenia. Moreover, TAK-418 improved memory deficits caused by aging or amyloid precursor protein overexpression. In contrast, TAK-418 did not improve memory deficits caused by miR-137 overexpression. Thus, miR-137 modulation may be involved in memory improvement by LSD1 inhibition. TAK-418 warrants further investigation as a novel therapeutic agent for diseases with epigenetic dysregulation.
Annual review of lysine-specific demethylase 1 (LSD1/KDM1A) inhibitors in 2021
Eur J Med Chem 2022 Jan 15;228:114042.PMID:34915312DOI:10.1016/j.ejmech.2021.114042.
Lysine-specific demethylase 1 (LSD1/KDM1A) has emerged as a promising epigenetic target for disease treatment. Several LSD1 inhibitors have advanced into clinical trials. Following our last annual review on LSD1 inhibitors in 2020 (Eur. J. Med. Chem. 2021, 214, 113254), in this review we aim to update LSD1 inhibitors including natural products, synthetic compounds and cyclic peptides reported during 2021. Design strategies, structure-activity relationships, binding model analysis and modes of action are highlighted. In particular, two FDA-approved antihypertensive drugs raloxifene and fenoldopam were repurposed as reversible LSD1 inhibitors. The clinical candidate TAK-418 for treating neurodevelopmental disorders and PET imaging agent [18F]30 for LSD1 were identified. Moreover, dual inhibitors targeting both LSD1 and HDAC6 or tubulin displayed enhanced anti-cancer effects than single agents. These compounds further enrich the structural types of LSD1 inhibitors.
Design, synthesis, and structure-activity relationship of TAK-418 and its derivatives as a novel series of LSD1 inhibitors with lowered risk of hematological side effects
Eur J Med Chem 2022 Sep 5;239:114522.PMID:35749987DOI:10.1016/j.ejmech.2022.114522.
Lysine-specific demethylase 1 (LSD1) is an enzyme that demethylates methylated histone H3 lysine 4 (H3K4). Inhibition of LSD1 enzyme activity could increase H3K4 methylation levels and treat diseases associated with epigenetic dysregulation. However, known LSD1 inhibitors disrupt the interaction between LSD1 and cofactors such as GFI1B, causing the risk of hematological toxicity, including thrombocytopenia. Starting from a known LSD1 inhibitor (±)1 as a lead compound, a novel series of LSD1 inhibitors that do not induce the expression of GFI1 mRNA, an in vitro surrogate marker of LSD1-GFI1B dissociation, has been designed and synthesized. Initial structure-activity relationship (SAR) studies revealed the structural features key to avoiding GFI1 mRNA induction. Such SAR information enables optimization of LSD1 inhibitors with lowered risk of hematological side effects; TAK-418 ((1R,2R)-2n), the clinical candidate compound found through this optimization, has a hematological safety profile in rodents and humans. We further confirmed that oral administration of TAK-418 at 0.3 and 1 mg/kg for 2 weeks ameliorated memory deficits in mice with NMDA receptor hypofunction, suggesting potential of efficacy in neurodevelopmental disorders. TAK-418 warrants further investigation as a novel class of LSD1 inhibitors with a superior safety profile for the treatment of CNS disorders.