product name WHI-P154
Description: WHI-P154 is a potent JAK3 inhibitor with IC50 of 1.8 μM, and displays no activity against JAK1 or JAK2, also inhibits EGFR, Src, Abl, VEGFR and MAPK, prevents Stat3, but not Stat5 phosphorylation. WHI-P154 also Inhibits STAT1 activation, iNOS expression and NO production in macrophages in vitro . Also inhibits other common kinases including EGFR (IC50 = 4 nM), Src, Abl, VEGFR, MAPK and PI 3-K and induces apoptosis in human glioblastoma cell lines (IC50 = 158 μ M).
References: Blood. 2008 Feb 15;111(4):2155-7; Clin Cancer Res. 1998 Oct;4(10):2463-71.
376.2
Formula
C16H14BrN3O3
CAS No.
211555-04-3
Storage
-20℃ for 3 years in powder form
-80℃ for 2 years in solvent
Solubility (In vitro)
DMSO: 71 mg/mL (199.3 mM)
Water: <1 mg/mL
Ethanol: <1 mg/mL
Solubility (In vivo)
30% propylene glycol, 5% Tween 80, 65% D5W: 30 mg/mL
Synonyms
other peoduct :References PubMed ID：:http://www.ncbi.nlm.nih.gov/pubmed/19417024/
| In Vitro |
In vitro activity: WHI-P154 is first described as a JAK3 inhibitor that displays no activity at JAK1 or JAK2. WHI-P154 inhibits STAT1 activation, iNOS expression and NO production in macrophages in vitro. But it is proved that WHI-P154 also inhibits other common kinases including EGFR, Src, Abl, VEGFR, MAPK and PI3-K and induces apoptosis in human glioblastoma cell lines. WHI-P154 inhibits glioblastoma cell adhesion and migration in the context of ECM. WHI-P154 exhibits significant cytotoxicity against U373 and U87 human glioblastoma cell lines, causing apoptotic cell death at micromolar concentrations. The in vitro antiglioblastoma activity of WHI-P154 is amplified > 200-fold and rendered selective by conjugation to recombinant human epidermal growth factor (EGF). In vitro treatment with EGF-P154 results killing of glioblastoma cells at nanomolar concentrations with an IC50 of 813 nM, whereas no cytotoxicity against EGF-R-negative leukemia cellsis observed, even at concentrations as high as 100 mM Kinase Assay: WHI-P154 is tested in kinase assays. The panel of kinases is selected to broadly cover the kinome, providing a good approximation of specificity. For all kinases, recombinant rat (IKKβ) or human (all others), full-length or GST-kinase domain fusion proteins, are used. WHI-P154 is inactive (concentration that inhibits response by 50% [IC50] > 30 μM) for the following kinases: AKT, AuroraA, cdk2, cdk6, CHK1, FGFR1, GSK3b, IKKb, IKKi, INSR, MAPK1, MAPKAP-K2, MASK, MET, PAK4, PDK1, PKCb, ROCK1, TaoK3, TrkA. Cell Assay: Cells are seeded into a 96-well plate at a density of 2.5×104 cells/well and incubated for 36 h at 37 ℃ before drug exposure. On the day of treatment, culture medium is carefully aspirated from the wells and replaced with fresh medium containing the quinazoline compounds WHI-P154 at concentrations ranging from 0.1 μM to 250 μM. Triplicate wells are used for each treatment. The cells are incubated with the compound for 24hours to 36hours at 37 ℃ in a humidified 5% CO2 atmosphere. To each well, 10 μL of MTT (final concentration, 0.5 mg/mL) is added, and the plate are incubated at 37 ℃ for 4 h. Than solubilized overnight at 37 ℃ in a solution containing 10% SDS in 0.01 M HCL. The absorbance of each well is measured in a microplate reader at 570 nm. |
|---|---|
| In Vivo | The in vivo administration of EGF-P154 results in delayed tumor progression and improved tumor-free survival in a severe combined immunodeficient mouse glioblastoma xenograft model. Whereas none of the control mice remain alive tumor-free beyond 33 days (median tumor-free survival, 19 days) and all control mice have tumors that rapidly progress to reach an average size of > 500 mm3 by 58 days, 40% of mice treated for 10 consecutive days with 1 mg/kg/day EGF-P154 remain alive and free of detectable tumors for more than 58 days with a median tumor-free survival of 40 days. The tumors developing in the remaining 60% of the mice never reache a size > 50 mm3. |
| Animal model | SCID Xenograft Model of Human Glioblastoma (U737) |
| Formulation & Dosage | Dissolved in PBS; 0.5 or 1 mg/kg; i.p. injection |
| References | Blood. 2008 Feb 15;111(4):2155-7; Clin Cancer Res. 1998 Oct;4(10):2463-71. |
