MK-1775 化学構造
分子量: 500.6

品質と確認

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Quality Control & MSDS

製品情報

  • Compare Wee1 Inhibitors
    Wee1阻害剤を比較
  • 研究分野
  • Combination Therapy
    併用療法

製品の説明

生物活性

情報 MK-1775は、有力で選択的なWee1</b> 阻害剤で、IC50 が 5.2 nMです。
目標

Wee1

IC50

5.2 nM [1]

In vitro試験 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. [1]
In vivo試験 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 models is also moderate. [1]
臨床試験 A Phase I dose escalation study evaluating MK-1775 in both monotherapy and in combination with Gemcitabine, Cisplatin, or Carboplatin in adult subjects with advanced solid tumors is currently ongoing.
特集 The first reported Wee1 inhibitor.

推薦された実験操作 (公開の文献だけ)

キナーゼアッセイ:

[1]

In vitro kinase assays 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.

細胞アッセイ:

[1]

細胞系 WiDr, NCI-H1299, TOV21G, and HeLa
濃度 Dissolved in DMSO, final concentrations ~10 μM
処理時間 24 hours
方法

Cells 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.

動物実験:

[1]

動物モデル Immunodeficient nude rats (F344/NJcl-rnu) bearing WiDr, HeLa-luc, or TOV21G-shp53 tumors
製剤 Prepared in a vehicle of 0.5% methylcellulose solution
投薬量 ~20 mg/kg/day
管理 Orally
Solubility 0.5% methylcellulose 30 mg/mL
* 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.

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

SpeciesBaboonDogMonkeyRabbitGuinea pigRatHamsterMouse
Weight (kg)121031.80.40.150.080.02
Body Surface Area (m2)0.60.50.240.150.050.0250.020.007
Km factor202012128653
Animal A (mg/kg) = Animal B (mg/kg) multiplied by  Animal B Km
Animal A Km

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×  mouse Km(3)  = 11.2 mg/kg
rat Km(6)
1

参考

化学情報

Download MK-1775 SDF
分子量 500.6
化学式

C27H32N8O2

CAS No. 955365-80-7
保管 2年-20℃
6月-80℃in DMSO
別名
溶解度 (25°C) * In vitro DMSO 80 mg/mL (159.8 mM)
0.0001 mg/mL (<1 mM)
エタノール <1 mg/mL (<1 mM)
In vivo 0.5% methylcellulose 30 mg/mL
* <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.
化学名 2-allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-6-(4-(4-methylpiperazin-1-yl)phenylamino)-1,2-dihydropyrazolo[3,4-d]pyrimidin-3-one

研究分野

カスタマーレビュー (6)


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Source Cancer Lett, 2014, 10.1016/j.canlet.2014.10.015. MK-1775 purchased from Selleck
Method H&E, PCNA staining, TUNEL assay
Cell Lines BxPC-3 xenograft model
Concentrations 20 mg/kg
Incubation Time 22 days
Results To further investigate the in vivo effects of MK-1775 and panobinostat treatment, tumors were analyzed by H&E, immunohistochemical, and TUNEL staining. Individual drug treatment resulted in increased tumor necrosis, which was further increased following combination treatment, as indicated by H&E staining (C). Proliferation was substantially lower in the combination group(MK-1775 and panobinostat) compared to the individual drug (MK-1775) treatment groups, as indicated by lower PCNA staining and significantly lower proliferation index values (D&E). MK-1775 treatment resulted in increased apoptosis, as measured by TUNEL assay and calculation of apoptotic indices, which was significantly increased in the combined drug treatment (F&G). These data highlight the potential for using combined MK-1775 and panobinostat for the treatment of pancreatic cancer.

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Source J Hematol Oncol, 2014, 7:53. MK-1775 purchased from Selleck
Method Western blot
Cell Lines AML, HL-60, HL-60/Ara-C cells
Concentrations 125, 250, 500 uM
Incubation Time 48 h
Results There was a concentration-dependent increase in apoptotic cells for the HL60/Ara-C cell line, whereas the parental cell line remained relatively unaffected by MK-1775 concentrations up to 500 nM. A concentration-dependent decrease in p-CDK1 and p-CDK2 accompanied by increase of γH2AX was detected in cells from patient AML#10 as well as in HL60/Ara-C. HL60 cells treated with 500 nM MK-1775 had a small increase of γH2AX and no change in p-CDK1 or p-CDK2, probably due to very low levels of expression prior to drug treatment.

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Source Mol Cancer Ther, 2012, 11(1), 174-82. MK-1775 purchased from Selleck
Method Fow cytometry/Western blotting
Cell Lines U2OS cells
Concentrations 300/1000 nM
Incubation Time 1 h
Results Inhibition of WEE1 kinase by MK-1775 led to increased uptake of the nucleoside analog EdU during the 30 to 90 min after MK-1775 addition (Fig. A). MK-1775 also led to decreased tyrosine 15 inhibitory phosphorylation on CDK1 and increased phosphorylation of CDK substrates. We found that inhibition of WEE1 markedly reduced the replication fork rates (Fig. C). depletion of CDT1 could normalize fork speed in response to WEE1 inhibition by MK-1775.

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Rating
Source Endocrinology, 2013, 154(9), 3219-27. MK-1775 purchased from Selleck
Method Western blot
Cell Lines T47D cells
Concentrations 1 uM
Incubation Time 2 h
Results To examine how ERK is activated in T47D cells, specific inhibitors of JAK2 (AZD1480) and EGFR (AG1478) were used. It found that pharmacological blockade of either EGFR or JAK2 reduced the phosphorylation of both STAT5 and ERK by GH.

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Source PLoS One, 2013, 8(3), e57523. MK-1775 purchased from Selleck
Method Histopathological assessment
Cell Lines
Concentrations 30 mg/kg
Incubation Time 48 h
Results Additionally, the tumor cells in the MK-1775 alone and MK-1775+ gemcitabine groups exhibited increased cell size with abundant eosinophilic cytoplasm and significant osteoid production, consistent with differentiation. tumors treated with MK-1775 alone and with MK-1775+ gemcitabine had an increased Ki67 index of 73% and 79%. In the vehicle-and gemcitabine-treated tumors, caspase activity was observed in 2% and 6% of tumor cells, respectively. Despite the lack of apoptotic cell death, gemcitabine-treated tumors revealed a significant increase (96%) in γH2AX immunoreactivity compared to the control groups, demonstrating that treatment causes DNA damage but fails to induce cytotoxic response.

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Rating
Source Oncol Rep, 2014, 32(5), 1991-8. MK-1775 purchased from Selleck
Method Immunofluorescence
Cell Lines HT29 cells
Concentrations 1 uM
Incubation Time 2 h
Results HT29 cells were treated with the indicated doses of AZD1480 for 2 h prior to the 2 h stimulation with IL-6. The cells were fixed and stained by the anti-phosphorylated STAT3 primary antibody and the FITC-conjugated secondary antibody. The nucleus was stained with DAPI. Figure shows that phosphorylated STAT3 and non-activated STAT3 are almost located in the cytoplasm instead of the nucleus. Thus, STAT3 translocates to the nucleus when activated.

製品表彰状 (8)

技術サポート&よくある質問(FAQ)

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