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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]. | [in vivo]
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 Ucp2mRNA 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]. | [IC 50]
KDM1/LSD1 | [References]
[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. DOI:10.1126/sciadv.aba1187
[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 DOI:10.1016/j.omtm.2021.02.011 |
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