ArticleNeuropsychopharmacology : official publication of the American College of Neuropsychopharmacology2019
T-448, a specific inhibitor of LSD1 enzyme activity, improves learning function without causing thrombocytopenia in mice.
Article in Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 45 citations in OpenAlex.
- Safety, pharmacokinetics and pharmacodynamics of TAK-418, a novel inhibitor of the epigenetic modulator lysine-specific demethylase 1A.British journal of clinical pharmacology · 2021Trial
- Liquid Chromatography/tandem Mass Spectrometry-based Target Engagement of Lysine-specific Demethylase 1 Inhibitor TAK-418 Through Detecting Covalent Adducts in the Brain.The AAPS journal · 2026Article
- Comparative analysis for optimal LSD1 inhibitors evaluation techniques: pros and cons.Journal of pharmaceutical analysis · 2026Review
- Histone demethylase inhibitors: developmental insights and current status.Future medicinal chemistry · 2025Review
- CoREST in pieces: Dismantling the CoREST complex for cancer therapy and beyond.Science advances · 2025Review
- Review
- Covalent adduct Grob fragmentation underlies LSD1 demethylase-specific inhibitor mechanism of action and resistance.Nature communications · 2025Article
- LPS-induced neuroinflammation induces changes in the transcriptional profile of members of the CoRest repressive complex in the hippocampus.Molecular biology reports · 2024Article
- Effect of histone demethylase KDM5B on long-term cognitive impairment in neonatal rats induced by sevoflurane.Frontiers in molecular neuroscience · 2024Article
- Targeting epigenetic regulators for inflammation: Mechanisms and intervention therapy.MedComm · 2022Review
- Sanguinarine, identified as a natural alkaloid LSD1 inhibitor, suppresses lung cancer cell growth and migration.Iranian journal of basic medical sciences · 2022Article
- Intrinsic and acquired drug resistance to LSD1 inhibitors in small cell lung cancer occurs through a TEAD4-driven transcriptional state.Molecular oncology · 2022Article
- The progress of research on histone methylation in ischemic stroke pathogenesis.Journal of physiology and biochemistry · 2022Review
- Biological and therapeutic role of LSD1 in Alzheimer's diseases.Frontiers in pharmacology · 2022Review
- Midazolam impacts acetyl-And butyrylcholinesterase genes: An epigenetic explanation for postoperative delirium?PloS one · 2022Article
- LSD1 enzyme inhibitor TAK-418 unlocks aberrant epigenetic machinery and improves autism symptoms in neurodevelopmental disorder models.Science advances · 2021Article
- Pharmacologic inhibition of lysine-specific demethylase 1 as a therapeutic and immune-sensitization strategy in pediatric high-grade glioma.Neuro-oncology · 2020Article
- Exploration of 5-cyano-6-phenylpyrimidin derivatives containing an 1,2,3-triazole moiety as potent FAD-based LSD1 inhibitors.Acta pharmaceutica Sinica. B · 2020Article
- Modulation of KDM1A with vafidemstat rescues memory deficit and behavioral alterations.PloS one · 2020Article
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Authors and funding
17 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Dysregulation of histone H3 lysine 4 (H3K4) methylation has been implicated in the pathogenesis of several neurodevelopmental disorders. Targeting lysine-specific demethylase 1 (LSD1), an H3K4 demethylase, is therefore a promising approach to treat these disorders. However, LSD1 forms complexes with cofactors including growth factor independent 1B (GFI1B), a critical regulator of hematopoietic differentiation. Known tranylcypromine-based irreversible LSD1 inhibitors bind to coenzyme flavin adenine dinucleotide (FAD) and disrupt the LSD1-GFI1B complex, which is associated with hematotoxicity such as thrombocytopenia, representing a major hurdle in the development of LSD1 inhibitors as therapeutic agents. To discover LSD1 inhibitors with potent epigenetic modulation and lower risk of hematotoxicity, we screened small molecules that enhance H3K4 methylation by the inhibition of LSD1 enzyme activity in primary cultured rat neurons but have little impact on LSD1-GFI1B complex in human TF-1a erythroblasts. Here we report the discovery of a specific inhibitor of LSD1 enzyme activity, T-448 (3-((1S,2R)-2-(cyclobutylamino)cyclopropyl)-N-(5-methyl-1,3,4-thiadiazol-2-yl)benzamide fumarate). T-448 has minimal impact on the LSD1-GFI1B complex and a superior hematological safety profile in mice via the generation of a compact formyl-FAD adduct. T-448 increased brain H3K4 methylation and partially restored learning function in mice with NMDA receptor hypofunction. T-448-type LSD1 inhibitors with improved safety profiles may provide unique therapeutic approaches for central nervous system disorders associated with epigenetic dysregulation.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.