BMS-911543

製品コードS7144 バッチS714401

印刷

化学情報

Chemical Structure Synonyms Storage
(From the date of receipt)		 3 years -20°C powder
1 years -80°C in solvent
化学式

C23H28N8O
分子量 432.52 CAS No. 1271022-90-2
Solubility (25°C)* 体外 DMSO 36 mg/mL (83.23 mM)
Ethanol 22 mg/mL (50.86 mM)
Water Insoluble
体内 （毎回新しく調製した物を用意してください）
Homogeneous suspension
CMC-NA
≥5mg/ml Taking the 1 mL working solution as an example, add 5 mg of this product to 1 ml of CMC-Na solution, mix evenly to obtain a homogeneous suspension with a final concentration of 5 mg/ml.
* <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.

溶剤液（一定の濃度）を調合する

生物活性

製品説明 BMS-911543 is a potent and selective inhibitor of JAK2 with IC50 of 1.1 nM, ~350-, 75- and 65-fold selective to JAK1, JAK3 and TYK2, respectively. Phase 1/2.
in vitro BMS-911543 shows potent antiproliferative activity in the SET-2 as well as BaF3-V617F engineered cell lines (both dependent upon JAK2 pathway), with IC50 values of 60 and 70 nM, respectively. The antiproliferative activity of this compound in SET-2 and BaF3-V617F cells correlates with similar activity on constitutively active pSTAT5 (IC50 80 and 65 nM, respectively). In contrast, non-JAK2-dependent cell lines (A549, MDA-MB-231, MiaPaCa-2) are significantly less sensitive to the inhibitor treatment. The excellent biochemical selectivity versus JAK1/3 translates to good cellular and functional selectivity in an IL-2 mediated T-cell proliferation assay (IC50 990 nM). Also, cell lines that rely on other JAK family members, including CTLL2 and parental BaF3 cells stimulated with IL-3, shows weak antiproliferative activity for this chemical (IC50 2.9 and 3.5 μM, respectively)[1].
in vivo BMS-911543 suppresses the pSTAT5 levels (mediated by wild type JAK2) relative to vehicle control when stimulated with thrombopoetin (TPO) in a mouse pharmacodynamic model. The responses are dose dependent and results in nearly complete normalization of pSTAT5 levels for 18 h at the highest oral dose of 30 mg/kg. At an intermediate 10 mg/kg oral dose, ∼65% reduction is observed up to 18 h, whereas at the 5 mg/kg dose, approximately 50% reduction in pSTAT5 for 8 h is achieved. Observed pSTAT5 reductions correlates with exposures of this compound, with AUC0–8h values of 23, 41, and 109 μM·h, respectively, for dose levels of 5, 10, and 30 mg/kg. In addition, this chemical demonstrates a potent and sustained (2 mg/kg up to 7 h) PD effect in blocking pSTAT5 formation in mice grafted with human SET-2 cells harboring JAK2-V617F mutation. The absolute oral bioavailability in solution is >50% in mice, rats, dogs, and monkeys. In addition, the absorption of this compound is not significantly impacted by particle dissolution (suspension formulation), with a relative bioavailability (vs solution) of ∼60% in rats and ∼100% in dogs[1].

プロトコル(参考用のみ)

細胞アッセイ 細胞株 Ba/F3 and SET2 cell lines
濃度
反応時間 2 h
実験の流れ Evaluation of BMS-911543 effects on Ba/F3 and SET2 cell lines or tumor xenograft lysates was performed by western blotting. For cell lines, roughly 500 000 cells per mL of media were incubated with this compound in dose-response format for 2 h, and subsequently processed for western blotting for p-STAT5, total STAT5 protein antibodies, p-STAT3, STAT3, ID1, PIM1, pSTAT1, or STAT1 at 1:400 dilution.
動物実験 動物モデル BALB/c mice
投薬量 10 mg/kg
投与方法 by oral gavage

参考

  • https://pubmed.ncbi.nlm.nih.gov/26288683/

Selleckの高級品が、幾つかの出版された研究調査結果（以下を含む）で使われた：

Novel JAK Inhibitors to Reduce Graft-Versus-Host Disease after Allogeneic Hematopoietic Cell Transplantation in a Preclinical Mouse Model [ Molecules, 2024, 29(8)1801] PubMed: 38675621
IL-6/JAK2-dependent G6PD phosphorylation promotes nucleotide synthesis and supports tumor growth [ Mol Metab, 2023, 10.1016/j.molmet.2023.101836] PubMed: 37949355
Acquired JAK2 mutations confer resistance to JAK inhibitors in cell models of acute lymphoblastic leukemia [ NPJ Precis Oncol, 2021, 5(1):75] PubMed: 34376782
Quantitative proteomics analysis identifies MUC1 as an effect sensor of EGFR inhibition. [ Oncogene, 2019, 38(9):1477-1488] PubMed: 30305724
MAPK pathway activity plays a key role in PD-L1 expression of lung adenocarcinoma cells [ J Pathol, 2019, 10.1002/path.5280] PubMed: 30972766
Mechanism and prognostic value of indoleamine 2,3-dioxygenase 1 expressed in hepatocellular carcinoma [Li S Cancer Sci, 2018, 109(12):3726-3736] PubMed: 30264546

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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