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Synonyms | N/A | Storage (From the date of receipt) |
3 years -20°C powder 1 years -80°C in solvent |
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化学式 | C23H21N5O3 |
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分子量 | 415.44 | CAS No. | 1300031-49-5 | |
Solubility (25°C)* | 体外 | DMSO | 83 mg/mL (199.78 mM) | |
Ethanol | 83 mg/mL (199.78 mM) | |||
Water | Insoluble | |||
* <1 mg/ml means slightly soluble or insoluble. * Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations. |
製品説明 | I-BET151 (GSK1210151A) is a novel selective BET inhibitor for BRD2, BRD3 and BRD4 with IC50 of 0.5 μM, 0.25 μM, and 0.79 μM in cell-free assays, respectively. |
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in vitro | I-BET151 exhibits potent selectivity over an extensive range of diverse protein types such as COX-2, P450, Aurora B, GSK3β, PI3K-γ, GPCR, ion channels, and transporters. Similar to I-BET762 (GSK525762A), I-BET151 displays potent binding affinity to BRD2, BRD3 and BRD4 with KD of 0.02-0.1 μM, and significantly inhibits lipopolysaccharide-stimulated IL-6 cytokine production in human peripheral blood mononuclear cells (PBMC) and whole blood (WB) as well as rat WB with IC50 of 0.16 μM, 1.26 μM, and 1.26 μM, respectively. I-BET151 (0.5 or 5 μM) inhibits the binding of BETs (BRD2, BRD3, BRD4, and BRD9) but not the binding of 23 other bromodomain proteins in HL60 nuclear extract to acetylated histone peptides. I-BET151 has potent efficacy against cell lines harboring different MLL-fusions such as MV4;11, RS4;11, MOLM13, and NOMO1 cells with IC50 of 15-192 nM. Consistently, I-BET151 completely ablates the colony-forming potential of MLL-fusion-driven leukaemias (MOLM13) but not leukaemias driven by tyrosine kinase activation (K562). I-BET151 also displays potent efficacy in both liquid culture and clonogenic assays using primary murine progenitors transformed with either MLL-ENL or MLL-AF9. I-BET151 treatment significantly induces apoptosis and prominent G0/G1 arrest in MLL-fusion cell lines driven by distinct MLL fusions (MOLM13 and MV4;11 containing MLL-AF9 and MLL-AF4, respectively) but not the K562 cells, probably due to the inhibition of transcription of BCL2, C-MYC and CDK6 by blocking the recruitment of BRD3/4, PAFc and SEC components into transcriptional start site (TSS). [1] |
in vivo | Administration of I-BET151 at 30 mg/kg/day significantly inhibits tumor growth of murine MLL-AF9 and human MLL-AF4 leukaemia in mice, and provides marked survival benefit. [1] |
特徴 | Optimized to retain excellent BET target potency and selectivity while enhancing the in vivo pharmacokinetics and terminal half-life to enable prolonged in vivo studies. |
キナーゼアッセイ | Fluorescence anisotropy (FP) ligand displacement assay | |
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All components are dissolved in buffer of composition 50 mM HEPES pH 7.4, 150 mM NaCl and 0.5 mM CHAPS with final concentrations of BRD 2/3/4 75 nM, fluorescent ligand 5 nM. 10 μL of this reaction mixture is added using a micro multidrop to wells containing 100 nL of various concentrations of I-BET151 or DMSO vehicle (1% final) in Greiner 384 well Black low volume microtitre plate and equilibrated in the dark for 60 minutes at room temperature. Fluorescence anisotropy is read in Envision (lex = 485 nm, lEM = 530 nm; Dichroic = 505 nM). | ||
細胞アッセイ | 細胞株 | MV4;11, MOLM13, NOMO1, RS4;11, HEL, HL60 and K562 |
濃度 | Dissolved in DMSO, final concentrations ~100 μM | |
反応時間 | 24, or 72 hours | |
実験の流れ | Cells are exposed to various concentrations of I-BET151 for 24 or 72 hours in 384-well or 96-well plates. For cell growth inhibition assays, plates are added with CellTiter-Glo reagent using a volume equivalent to the cell culture volume in the wells, shaken for approximately 2 minutes and chemiluminescent signal is read on the Analyst GT or EnVision Plate Reader. For cell proliferation assays, CellTiter-Aqueous One is added to each well and plates are incubated for 4 hours at 37 °C. Absorbance is read at 490 nm on a SpectraMax Gemini reader |
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動物実験 | 動物モデル | NOD-SCID mice injected intravenously with MV4;11 cells, and C57BL/6 mice injected intravenously with MLL-AF9 cells |
投薬量 | ~30 mg/kg/day | |
投与方法 | Intraperitoneal injection |
Data from [Data independently produced by , , Theranostics, 2016, 6(2):219-30.]
Data from [Data independently produced by , , Oncotarget, 2016, 7(3):2545-54]
Data from [Data independently produced by , , J Immunol, 2018, 201(9):2744-2752]
A Crispr Screen of HIV Dependency Factors to Identify Host Proteins Necessary for Activation of Latent HIV Proviruses [ ResearchWorks Archive, 2024, ] | PubMed: none |
Inhibition of neutral sphingomyelinase 2 impairs HIV-1 envelope formation and substantially delays or eliminates viral rebound [ Proc Natl Acad Sci U S A, 2023, 120(28):e2219543120] | PubMed: 37406092 |
RUNX1 colludes with NOTCH1 to reprogram chromatin in T cell acute lymphoblastic leukemia [ iScience, 2023, 26(6):106795] | PubMed: 37213235 |
Enhancer Clusters Drive Type I Interferon-Induced TRAIL Overexpression in Cancer, and Its Intracellular Protein Accumulation Fails to Induce Apoptosis [ Cancers (Basel), 2023, 15(3)967] | PubMed: 36765925 |
A CRISPR Screen of HIV Dependency Factors Reveals That CCNT1 Is Non-Essential in T Cells but Required for HIV-1 Reactivation from Latency [ Viruses, 2023, 15(9)1863] | PubMed: 37766271 |
A CRISPR Screen of HIV Dependency Factors Reveals That CCNT1 Is Non-Essential in T Cells but Required for HIV-1 Reactivation from Latency [ Viruses, 2023, 15(9)1863] | PubMed: 37766271 |
A CRISPR screen of HIV dependency factors reveals CCNT1 is non-essential in T cells but required for HIV-1 reactivation from latency [ bioRxiv, 2023, 2023.07.28.551016] | PubMed: 37546973 |
Molecular Signature Predictive of Long-Term Liver Fibrosis Progression to Inform Antifibrotic Drug Development [ Gastroenterology, 2022, 162(4):1210-1225] | PubMed: 34951993 |
Deregulation and epigenetic modification of BCL2-family genes cause resistance to venetoclax in hematologic malignancies [ Blood, 2022, blood.2021014304] | PubMed: 35704690 |
Bromodomain-containing protein 4 (BRD4) as an epigenetic regulator of fatty acid metabolism genes and ferroptosis [ Cell Death Dis, 2022, 13(10):912] | PubMed: 36309482 |
長期の保管のために-20°Cの下で製品を保ってください。
人間や獣医の診断であるか治療的な使用のためにでない。
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