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
* <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 BMS-911543 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 BMS-911543 (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 BMS-911543, with AUC0–8h values of 23, 41, and 109 μM·h, respectively, for dose levels of 5, 10, and 30 mg/kg. In addition, BMS-911543 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 BMS-911543 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 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

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：

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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