Antibodies
BMS-911543
- 貨號 Cat. No.
- S7144
- 規格 Size
- 5~200mg
- 品牌 Brand
- Selleckchem
Description
BMS-911543
Catalog No.S7144
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.
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Biological Activity
| Description | 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. | |||||
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| Targets | JAK2 | |||||
| IC50 | 1.1 nM [1] | |||||
| In vitro | BMS-911543 is a pyrrolopyridine small-molecule inhibitor. Dissociation constants of BMS-911543 for JAK1, JAK2 and JAK3 extended these findings and displays a broader selectivity for JAK2 with Ki values of 1114, 0.48 and 357 nm, respectively. Outside the JAK family, the highest inhibitory activity is observed for the Src family member, Lyn (IC50=300 nm), and the c-FMS receptor tyrosine kinase (IC50=450 nm), which are both significantly less sensitive than JAK2 (>250-fold). In JAK2V617F-dependent cells such as SET2 or Ba/F3 engineered to express JAK2V617F, BMS-911543 treatment resulted in a dose-dependent anti-proliferative effect with IC50 values of 60 and 70 nm, respectively. BMS-911543 suppresses the growth of MPN patient-derived cells. In the presence of EPO, BFU-E IC50s for BMS-911543 in MPN-patient cells rangs from <0.150 to ~0.9 μm, indicating an increased sensitivity to JAK2 inhibition compared with normal healthy volunteers. BMS-911543 inhibits TPO-stimulated JAK2WT-pSTAT5 activity in human platelets ex vivo but not upon IL-2- or IL-4-stimulated JAK1/JAK3-pSTAT responses in human T cells. [1] | |||||
| In vivo | BMS-911543 is also highly active in in vivo models of JAK2 signaling, with sustained pathway suppression being observed after a single oral dose. At low dose levels active in JAK2-dependent PD models, no effects are observed in an in vivo model of immunosuppression monitoring antigen-induced IgG and IgM production. [1] | |||||
| Features | ||||||
Protocol(Only for Reference)
Kinase Assay:
| Biochemical kinase assays | Incubation mixtures included: 1.1 nm JAK2, 1.5 μm peptide substrate (5-FAM-KKKKEEIYFFFG-OH for JAK2) and 30 μm ATP. The reaction mixture is analyzed on a Caliper LabChip 3000 by electrophoretic separation of the fluorescent substrate and phosphorylated product after 180 min. The inhibitory activity of BMS-911543 against multiple other recombinant enzymes is evaluated using similar methodology in kinase assays or for interaction with over 450 kinases at 1 μm in collaboration with Ambit Biosciences using competition-binding assays. For enzyme kinetics, BMS-911543 is tested from 42 pm to 8.33 μm against JAK1, JAK2 or JAK3. All kinase reactions are carried out at room temperature with γ-[33 P]-labeled ATP at 3.75–100 μm for 30 min and terminated by the addition of 1%phosphoric acid. Phosphorylated peptide is captured on 96-well phosphocellulose filter plates using a vacuum manifold and quantified using scintillation counting. |
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Cell Assay:
| Cell lines | SET2 or Ba/F3 cell lines |
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| Concentrations | 10, 3.3, 1.1, 0.4 and 0.1 μm |
| Incubation Time | 72 h |
| Method | The anti-proliferative effects of BMS-911543 on tumor cell lines are monitored by [3H] thymidine incorporation. Cells are incubated with stepwise dilutions of compound for 72 h in RPMI media supplemented with 10% fetal bovine serum. On day 4, 0.022 μCi/ml of [3H] thymidine is added to each well and allowed to incubate for 3–4 h. Cells are harvested onto filter plates, washed and processed for incorporated radioactivity on a scintillation counter. In certain instances, Ba/F3-engineered cells are propagated in the presence of recombinant human erythropoietin or recombinant mouse IL-3. SET2 or Ba/F3 cell lines are treated with BMS-911543 as indicated in the results section and processed for the induction of apoptosis via fluorescence-activated cell sorting (FACS) analysis using annexin V surface staining following the manufacturer’s instructions. Percent apoptosis is expressed as the level of annexin V staining observed versus dimethylsulfoxide control under the same treatment conditions. |
Animal Study:
| Animal Models | BALB/c mice |
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| Dosages | 5, 10 and 30 mg/kg |
| Administration | oral |
References
Clinical Trial Information( data from http://clinicaltrials.gov)
| NCT Number | Recruitment | Conditions | Sponsor /Collaborators | Start Date | Phases |
|---|---|---|---|---|---|
| NCT01236352 | Recruiting | Cancer | Bristol-Myers Squibb | 2011-05 | Phase 1|Phase 2 |
Chemical Information
| Molecular Weight (MW) | 432.52 |
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| Formula | C23H28N8O |
| CAS No. | 1271022-90-2 |
| Storage | 3 years -20℃Powder |
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| 6 months-80℃in DMSO | |
| Syonnyms | N/A |
| Solubility (25°C) * | In vitro | DMSO | mg/mL (<1 mM) |
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| Water | mg/mL (<1 mM) | ||
| Ethanol | mg/mL (<1 mM) | ||
| * <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. | |||
| Chemical Name | Imidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide, N,N-dicyclopropyl-4-[(1,5-dimethyl-1H-pyrazol-3-yl)amino]-6-ethyl-1,6-dihydro-1-methyl- |
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