CAS NO: | 955365-80-7 |
规格: | ≥98% |
包装 | 价格(元) |
10mg | 电议 |
25mg | 电议 |
50mg | 电议 |
100mg | 电议 |
250mg | 电议 |
500mg | 电议 |
1g | 电议 |
Molecular Weight (MW) | 500.6 |
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Formula | C27H32N8O2 |
CAS No. | 955365-80-7 |
Storage | -20℃ for 3 years in powder form |
-80℃ for 2 years in solvent | |
Solubility (In vitro) | DMSO: 80 mg/mL (159.8 mM) |
Water: <1 mg/mL | |
Ethanol: <1 mg/mL | |
Solubility (In vivo) | 2% DMSO+30% PEG 300+5% Tween+ddH2O: 5 mg/mL |
Synonyms | AZD-1775; MK-1775; AZD1775; MK1775; AZD-1775; AZD 1775; MK 1775; adavosertib. |
In Vitro | In vitro activity: MK-1775 inhibits Wee1 kinase in an ATP-competitive manner. Compared to Wee1, MK-1775 displays 2- to 3-fold less potency against Yes with IC50 of 14 nM, 10-fold less potency against seven other kinases with>80% inhibition at 1 μM, and>100-fold selectivity over human Myt 1, another kinase that inhibits cyclin-dependent kinase 1 (CDC2) by phosphorylation at an alternative site (Thr14). By abrogating the DNA damage checkpoint via blockade of Wee1 activity in WiDr cells bearing mutated p53, MK-1775 treatment inhibits the basal phosphorylation of CDC2 at Tyr15 (CDC2Y15) with EC50 of 49 nM, and suppresses gemcitabine-, carboplatin- or cisplatin-induced phosphorylation of CDC2 and cell cycle arrest in a dose-dependent manner, with EC50 of 82 nM and 81 nM, 180 nM and 163 nM, as well as 159 nM and 160 nM, respectively. MK-1775 treatment alone at 30-100 nM has no significant antiproliferative effect in WiDr and H1299 cells, whereas MK-1775 at 300 nM, sufficient to inhibit Wee1 by>80%, displays moderate but significant antiproliferative effects by 34.1% in WiDr cells and 28.4% in H1299 cells. Kinase Assay: Recombinant human Wee1 is used. Kinase reaction is conducted with 10 μM ATP, 1.0 μCi of [γ-33P]ATP, and 2.5 μg of poly(Lys, Tyr) as a substrate in the presence of increasing concentrations of MK-1775 at 30°C for 30 minutes. Radioactivity incorporated into the substrate is trapped on MultiScreen-PH plates and is counted on a liquid scintillation counter. Cell Assay: Cells (WiDr, NCI-H1299, TOV21G, and HeLa) are treated with or without gemcitabine for 24 hours, then with MK-1775 for an additional 24 hours. Cell viability is determined with a WST-8 kit using SpectraMax. Cellular caspase-3/7 activities are determined with a Caspase-3/7 Glo kit. |
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In Vivo | MK-1775 treatment alone at ~20 mg/kg displays minimal antitumor effects against WiDr xenografts in rats with T/C of 69% at day 3. Antitumor efficacy by MK-1775 alone in the nude rat HeLa-luc and TOV21G-shp53 xenograft models is also moderate. |
Animal model | Immunodeficient nude rats (F344/NJcl-rnu) bearing WiDr, HeLa-luc, or TOV21G-shp53 tumors |
Formulation & Dosage | Dissolved in a vehicle of 0.5% methylcellulose solution; 20 mg/kg/day; oral gavage |
References | Mol Cancer Ther. 2009 Nov;8(11):2992-3000. |