7XW8

Crystal structure of Lysine Specific Demethylase 1 (LSD1) with TAK-418 distomer, FAD-adduct

Summary for 7XW8

• Entry DOI: 10.2210/pdb7xw8/pdb
• Related: 7E0G
• Descriptor: Lysine-specific histone demethylase 1A, GLYCEROL, MAGNESIUM ION, ... (6 entities in total)
• Functional Keywords: inhibitor, tak-418, distomer, fad-adduct, oxidoreductase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 75049.04

Authors

Oki, H. (deposition date: 2022-05-26, release date: 2022-10-12, Last modification date: 2023-11-29)

Primary citation

Hattori, Y.,Matsumoto, S.,Morimoto, S.,Daini, M.,Toyofuku, M.,Matsuda, S.,Baba, R.,Murakami, K.,Iwatani, M.,Oki, H.,Iwasaki, S.,Matsumiya, K.,Tominari, Y.,Kimura, H.,Ito, M.
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., 239:114522-114522, 2022

PubMed Abstract: 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.

PubMed: 35749987
DOI: 10.1016/j.ejmech.2022.114522

Experimental method

X-RAY DIFFRACTION (2.28 Å)