8INL
LSD1 in complex with S2172
Summary for 8INL
| Entry DOI | 10.2210/pdb8inl/pdb |
| Descriptor | Lysine-specific histone demethylase 1A, L(+)-TARTARIC ACID, GLYCEROL, ... (6 entities in total) |
| Functional Keywords | demethylase, amine oxidase, chromatin, histone, fad, mechanism-based inhibitor, oxidoreductase-inhibitor complex, oxidoreductase/inhibitor |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 76005.42 |
| Authors | Niwa, H.,Sato, S.,Umehara, T. (deposition date: 2023-03-10, release date: 2024-03-13, Last modification date: 2024-12-25) |
| Primary citation | Shinjo, K.,Umehara, T.,Niwa, H.,Sato, S.,Katsushima, K.,Sato, S.,Wang, X.,Murofushi, Y.,Suzuki, M.M.,Koyama, H.,Kondo, Y. Novel pharmacologic inhibition of lysine-specific demethylase 1 as a potential therapeutic for glioblastoma. Cancer Gene Ther, 31:1884-1894, 2024 Cited by PubMed Abstract: Lysine-specific demethylase 1 (LSD1/KDM1A) is a pivotal epigenetic enzyme that contributes to several malignancies including malignant glioma. LSD1 is a flavin adenine dinucleotide dependent histone demethylase that specifically targets histone H3 lysine (K) 4 mono- (me1) and di-methylation (me2) and H3K9me1/2 for demethylation. Herein we report the development of an LSD inhibitor, S2172, which efficiently penetrates the blood-brain barrier. S2172 effectively suppresses LSD1 enzymatic activity, resulting in the depletion of cell growth both in vitro in glioma stem cells (GSCs) (mean half-maximal inhibitory concentration (IC) of 13.8 μM) and in vivo in a GSC orthotopic xenograft mouse model. Treatment with S2172 robustly reduced the expression of the stemness-related genes MYC and Nestin in GSC cells. Consistent with this, chromatin immunoprecipitation-sequencing revealed a significant S2172-dependent alteration in H3K4me2/H3K4me3 status. Furthermore, we identified 284 newly acquired H3K4me2 peak regions after S2172 treatment, which were encompassed within super-enhancer regions. The altered H3K4me2/H3K4me3 status induced by S2172 treatment affected the expression of genes related to tumorigenesis. Our data suggest that targeting LSD1 with S2172 could provide a promising treatment option for glioblastomas, particularly due to targeting of GSC populations. PubMed: 39501082DOI: 10.1038/s41417-024-00847-8 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.62 Å) |
Structure validation
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