| CAS NO: | 1271022-90-2 |
| 规格: | ≥98% |
| 包装 | 价格(元) |
| 2mg | 电议 |
| 5mg | 电议 |
| 10mg | 电议 |
| 25mg | 电议 |
| 50mg | 电议 |
| 100mg | 电议 |
| 250mg | 电议 |
| Molecular Weight (MW) | 432.52 |
|---|---|
| Formula | C23H28N8O |
| CAS No. | 1271022-90-2 |
| Storage | -20℃ for 3 years in powder form |
| -80℃ for 2 years in solvent | |
| Solubility (In vitro) | DMSO: 36 mg/mL (83.2 mM) |
| Water: <1 mg/mL | |
| Ethanol: 22 mg/mL (50.9 mM) | |
| Other info | Chemical Name: N,N-dicyclopropyl-4-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide SMILES Code: O=C(C1=CC2=C(N(C)C=N3)C3=C(NC4=NN(C)C(C)=C4)N=C2N1CC)N(C5CC5)C6CC6 |
| Synonyms | BMS 911543; BMS911543; BMS-911543. |
| In Vitro | In vitro activity: 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) Kinase Assay: BMS-911543 is a potent, selective and orally bioavailable inhibitor of JAK2 (Janus-associated kinase) with IC50 of 1.1 nM, ~350-, 75- and 65-fold selective to JAK1, JAK3 and TYK2, respectively. BMS-911543 selectively inhibits JAK2, thereby preventing the activation of JAK/STAT (signal transducer and activator of transcription) signaling cascade, including the activation of STAT3, which may lead to an induction of tumor cell apoptosis and a decrease in cellular proliferation. JAK2 is often upregulated or mutated in a variety of cancer cells, and it mediates STAT3 activation and plays a key role in tumor cell proliferation and survival. The inhibition activity and affinity against JAK2 are both much higher than those against JAK1 and JAK3. Besides that, BMS-911543 also has efficacy against other kinases, such as Lyn and the c-FMS receptor tyrosine kinase. In JAK-dependent cells such as SET2 or Ba/F3, the treatment of BMS-911543 causes an anti-proliferative effect with IC50 values of 60 and 70nM, respectively. Cell Assay: Human and murine pancreatic ductal adenocarcinoma (PDAC) tumor cells or PSC are cultured in 96 well plates and the following day treated with BMS-911543 or DMSO vehicle control for 48 hours. After 48 hours, MTT reagent (ATCC) is added for 2 hours at 37°C. Samples are analyzed on a plate reader testing for absorbance at 450 nM |
|---|---|
| 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. |
| Animal model | BALB/c mice |
| Formulation & Dosage | Dissolved in a polyethylene glycol 400 (PEG-400)/citrate buffer (80:20, v/v) solution; 10 mg/kg; administrated orally |
| References | ACS Med Chem Lett. 2015 Jul 12;6(8):850-5; Leukemia. 2012 Feb;26(2):280-8. |
Differential inhibitory sensitivity of JAK2V617F in vivo. Leukemia. 2012Feb;26(2):280-8. |
Effects of BMS-911543 on cytokine-dependent and -independent hematopoietic colony growth of MPN patients with activating JAK2 pathway mutations. Leukemia. 2012 Feb;26(2):280-8. |
Effects of BMS-911543 in a mouse model of immunosuppression. Leukemia. 2012 Feb;26(2):280-8.
Regulation of STAT1 as part of a JAK2-mediated transcriptional program. |
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