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Adavosertib (MK-1775)
別名：AZD1775
アダボセルチブ (Adavosertib (MK-1775、AZD1775)) は、無細胞アッセイで IC50 が 5.2 nM の強力かつ選択的な Wee1 阻害剤です。G2 DNA 損傷チェックポイントを阻害します。臨床フェーズ2。
CAS No. 955365-80-7
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Adavosertib (MK-1775)関連製品
| 関連製品 | PD0166285 | もっと見る |
|---|---|---|
| 関連化合物ライブラリー | Kinase Inhibitor Library PI3K/Akt Inhibitor Library MAPK Inhibitor Library DNA Damage/DNA Repair compound Library Cell Cycle compound library | もっと見る |
シグナル伝達経路
Wee1阻害剤の選択性比較
Cell Data
| Cell Lines | Assay Type | Concentration | Incubation Time | 活性情報 | PMID |
|---|---|---|---|---|---|
| CMY | Cell Viability Assay | 10-10000 nM | 72 h | reduces cell vialibity in a concentration-dependent manner | 24962331 |
| CMK | Cell Viability Assay | 10-10000 nM | 72 h | reduces cell vialibity in a concentration-dependent manner | 24962331 |
| MOLM-13 | Growth Inhibition Assay | 125/250/500 nM | 48 h | increases cell death in a concentration-dependent manner | 25084614 |
| OCI-AML3 | Growth Inhibition Assay | 125/250/500 nM | 48 h | increases cell death in a concentration-dependent manner | 25084614 |
| HL-60 | Growth Inhibition Assay | 125/250/500 nM | 48 h | increases cell death in a concentration-dependent manner | 25084614 |
| U937 | Growth Inhibition Assay | 125/250/500 nM | 48 h | increases cell death in a concentration-dependent manner | 25084614 |
| MV4-11 | Growth Inhibition Assay | 125/250/500 nM | 48 h | increases cell death in a concentration-dependent manner | 25084614 |
| THP-1 | Growth Inhibition Assay | 125/250/500 nM | 48 h | increases cell death in a concentration-dependent manner | 25084614 |
| SK-N-DZ | Apoptosis Assay | 500 nM | 48 h | induces cell apoptosis | 25308916 |
| SK-N-AS | Apoptosis Assay | 500 nM | 48 h | induces cell apoptosis | 25308916 |
| IST-MES1 | Cell Viability Assay | 150/250 nM | 72 h | enhances the cisplatin cytotoxic effect in a concentration-dependent manner | 24365782 |
| IST-MES2 | Cell Viability Assay | 150/250 nM | 72 h | enhances the cisplatin cytotoxic effect in a concentration-dependent manner | 24365782 |
| REN | Cell Viability Assay | 150/250 nM | 72 h | enhances the cisplatin cytotoxic effect in a concentration-dependent manner | 24365782 |
| NCI-H2452 | Cell Viability Assay | 150/250 nM | 72 h | enhances the cisplatin cytotoxic effect in a concentration-dependent manner | 24365782 |
| MSTO-211H | Cell Viability Assay | 150/250 nM | 72 h | enhances the cisplatin cytotoxic effect in a concentration-dependent manner | 24365782 |
| NCI-H2052 | Cell Viability Assay | 150/250 nM | 72 h | enhances the cisplatin cytotoxic effect in a concentration-dependent manner | 24365782 |
| T98G | Apoptosis Assay | 100/250 nM | 6 h | enhances radiation-induced cell killing | 21992793 |
| A549 | Apoptosis Assay | 200 nM | 1 h | radiosensitizes NSCLC cells in a p53-dependent manner | 21799033 |
| H460 | Apoptosis Assay | 200 nM | 1 h | radiosensitizes NSCLC cells in a p53-dependent manner | 21799033 |
| H1299 | Apoptosis Assay | 200 nM | 1 h | radiosensitizes NSCLC cells in a p53-dependent manner | 21799033 |
| Calu-6 | Apoptosis Assay | 200 nM | 1 h | radiosensitizes NSCLC cells in a p53-dependent manner | 21799033 |
| WiDr | Kinase Assays | 10-10000 nM | 8 h | inhibits phosphorylation of CDC2 at Tyr15 with an EC50 value of 85 nmol/L pretreated with gemcitabine | 19887545 |
| Function assay | MDA-MB-231 | 0.1 to 10 uM | 6 hrs | Inhibition of Wee1 in human MDA-MB-231 cells assessed as decrease in CDK1 phosphorylation at Tyr 15 at 0.1 to 10 uM after 6 hrs by Western blot method | 28792760 |
| Function assay | HEK293T | 0.1 to 10 uM | 6 hrs | Inhibition of Wee1 in HEK293T cells assessed as decrease in CDK1 phosphorylation at Tyr15 at 0.1 to 10 uM after 6 hrs by Western blot method | 28792760 |
| Function assay | HEK293T | 0.1 to 10 uM | 6 hrs | Inhibition of PLK1 in HEK293T cells assessed as decrease in TCTP phosphorylation at 0.1 to 10 uM after 6 hrs by Western blot method | 28792760 |
| Function assay | MDA-MB-23 | 0.1 to 10 uM | 6 hrs | Inhibition of PLK1 in human MDA-MB-23 cells assessed as decrease in TCTP phosphorylation at 0.1 to 10 uM after 6 hrs by Western blot method | 28792760 |
| Antiproliferative assay | MDA-MB-231 | 72 hrs | Antiproliferative activity against human MDA-MB-231 cells measured after 72 hrs by CellTiter-Blue assay, IC50 = 0.26 μM. | 28792760 | |
| Antiproliferative assay | HEK293T | 72 hrs | Antiproliferative activity against HEK293T cells measured after 72 hrs by CellTiter-Blue assay, IC50 = 0.29 μM. | 28792760 | |
| Antiproliferative assay | MM1S | 72 hrs | Antiproliferative activity against human MM1S cells measured after 72 hrs by CellTiter-Blue assay, IC50 = 0.31 μM. | 28792760 | |
| Function assay | HEK293 | 1 hr | Inhibition of human full length PKMYT1 expressed in HEK293 cells using EFS (247 to 259 residues) as substrate after 1 hr by fluorescence polarization immunoasay, Ki = 0.47 μM. | 29941193 | |
| Function assay | HEK293 | 1 hr | Inhibition of human full length PKMYT1 expressed in HEK293 cells using EFS (247 to 259 residues) as substrate after 1 hr by fluorescence polarization immunoasay, IC50 = 4.94 μM. | 29941193 | |
| Dayo | Growth Inhibition Assay | IC50=150 nM | 24661910 | ||
| SK-N-DZ | Growth Inhibition Assay | IC50=0.36 ± 0.01 μM | 25308916 | ||
| SK-N-AS | Growth Inhibition Assay | IC50=0.50 ± 0.02 μM | 25308916 | ||
| SK-N-BE (2), MK→PAN | Growth Inhibition Assay | IC50=2.4 ± 0.3 μM | 25308916 | ||
| SK-N-BE (2), PAN→MK | Growth Inhibition Assay | IC50=26.6 ± 9.6 μM | 25308916 | ||
| SK-N-BE (2) | Growth Inhibition Assay | IC50=2.4 ± 0.3 μM | 25308916 | ||
| PANC-1 | Growth Inhibition Assay | IC50=10.6 ± 1.1 μM | 25458954 | ||
| MIAPaCa-2 | Growth Inhibition Assay | IC50=0.5 ± 0.05 μM | 25458954 | ||
| HPAC | Growth Inhibition Assay | IC50=0.5 ± 0.01 μM | 25458954 | ||
| CFPAC-1 | Growth Inhibition Assay | IC50=3.3 ± 0.2 μM | 25458954 | ||
| BxPC-3 | Growth Inhibition Assay | IC50=0.8 ± 0.03 μM | 25458954 | ||
| ASPC-1 | Growth Inhibition Assay | IC50=13.2 ± 1.1 μM | 25458954 | ||
| UW228 | Growth Inhibition Assay | IC50=232 nM | 24661910 | ||
| WEE1 | Growth Inhibition Assay | IC50=5.2 nM | 23699655 | ||
| CDC2 | Growth Inhibition Assay | IC50＞1000 nM | 23699655 | ||
| CDK7 | Growth Inhibition Assay | IC50＞1000 nM | 23699655 | ||
| MYT1 | Growth Inhibition Assay | IC50=530 nM | 23699655 | ||
| Function assay | Expi293F | Binding affinity to recombinant human full-length N-terminal His8-tagged Wee1 (1 to 646 residues) expressed in human Expi293F cells assessed as dessociation constant by quantitative real-time PCR method, Kd = 0.0032 μM. | 28792760 | ||
| Function assay | Expi293F | Binding affinity to recombinant human full-length N-terminal His8-tagged Wee2 (1 to 567 residues) expressed in human Expi293F cells assessed as dessociation constant by quantitative real-time PCR method, Kd = 0.0039 μM. | 28792760 | ||
| qHTS assay | TC32 | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for TC32 cells | 29435139 | ||
| qHTS assay | U-2 OS | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for U-2 OS cells | 29435139 | ||
| qHTS assay | A673 | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for A673 cells | 29435139 | ||
| qHTS assay | DAOY | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for DAOY cells | 29435139 | ||
| qHTS assay | Saos-2 | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for Saos-2 cells | 29435139 | ||
| qHTS assay | BT-37 | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for BT-37 cells | 29435139 | ||
| qHTS assay | RD | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for RD cells | 29435139 | ||
| qHTS assay | SK-N-SH | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for SK-N-SH cells | 29435139 | ||
| qHTS assay | BT-12 | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for BT-12 cells | 29435139 | ||
| qHTS assay | NB1643 | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for NB1643 cells | 29435139 | ||
| qHTS assay | OHS-50 | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for OHS-50 cells | 29435139 | ||
| qHTS assay | BT-12 | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for BT-12 cells | 29435139 | ||
| qHTS assay | DAOY | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for DAOY cells | 29435139 | ||
| qHTS assay | SK-N-SH | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for SK-N-SH cells | 29435139 | ||
| qHTS assay | Rh41 | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for Rh41 cells | 29435139 | ||
| qHTS assay | A673 | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for A673 cells) | 29435139 | ||
| qHTS assay | MG 63 (6-TG R) | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for MG 63 (6-TG R) cells | 29435139 | ||
| qHTS assay | U-2 OS | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for U-2 OS cells | 29435139 | ||
| qHTS assay | OHS-50 | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for OHS-50 cells | 29435139 | ||
| qHTS assay | Rh41 | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for Rh41 cells | 29435139 | ||
| qHTS assay | RD | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for RD cells | 29435139 | ||
| qHTS assay | SJ-GBM2 | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for SJ-GBM2 cells | 29435139 | ||
| qHTS assay | SK-N-MC | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for SK-N-MC cells | 29435139 | ||
| qHTS assay | NB-EBc1 | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for NB-EBc1 cells | 29435139 | ||
| qHTS assay | LAN-5 | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for LAN-5 cells | 29435139 | ||
| qHTS assay | Rh18 | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for Rh18 cells | 29435139 | ||
| qHTS assay | SJ-GBM2 | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for SJ-GBM2 cells | 29435139 | ||
| qHTS assay | Saos-2 | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for Saos-2 cells | 29435139 | ||
| 他の多くの細胞株試験データをご覧になる場合はこちらをクリックして下さい | |||||
生物活性
| 製品説明 | アダボセルチブ (Adavosertib (MK-1775、AZD1775)) は、無細胞アッセイで IC50 が 5.2 nM の強力かつ選択的な Wee1 阻害剤です。G2 DNA 損傷チェックポイントを阻害します。臨床フェーズ2。 | ||
|---|---|---|---|
| 特性 | The first reported Wee1 inhibitor. | ||
| Targets |
|
| In Vitro | ||||
| In vitro | 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] | |||
|---|---|---|---|---|
| Kinase Assay | 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. | ||||
| 細胞実験 | 細胞株 | WiDr, NCI-H1299, TOV21G, and HeLa | ||
| 濃度 | Dissolved in DMSO, final concentrations ~10 μM | |||
| 反応時間 | 24 hours | |||
| 実験の流れ | 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. |
|||
| 実験結果図 | Methods | Biomarkers | 結果図 | PMID |
| Western blot | p-Cdk1(Y15) / Cdk1 p-KAP1(S824) / p-Chk2(T68) / p-Chk1(S345) PARP / CF-PARP / pH3(S10) / p-CDC25c(S216) / p-CDK2(Y15) WEE1 |
|
25609063 | |
| Immunofluorescence | tubulin / p-HH3(S10) γH2AX Cleaved caspase-3 / pH3 |
|
30755439 | |
| Growth inhibition assay | Cell viability IC50 |
|
25458954 | |
| In Vivo | ||
| 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. [1] | |
|---|---|---|
| 動物実験 | 動物モデル | Immunodeficient nude rats (F344/NJcl-rnu) bearing WiDr, HeLa-luc, or TOV21G-shp53 tumors |
| 投与量 | ~20 mg/kg/day | |
| 投与経路 | Orally | |
| NCT Number | Recruitment | Conditions | Sponsor/Collaborators | Start Date | Phases |
|---|---|---|---|---|---|
| NCT03253679 | Completed | Advanced Malignant Solid Neoplasm|Refractory Malignant Solid Neoplasm |
National Cancer Institute (NCI) |
January 16 2019 | Phase 2 |
| NCT03668340 | Active not recruiting | Uterine Cancer |
Dana-Farber Cancer Institute|AstraZeneca |
October 22 2018 | Phase 2 |
| NCT03028766 | Completed | Hypopharynx Squamous Cell Carcinoma|Oral Cavity Squamous Cell Carcinoma|Larynx Cancer |
University of Birmingham|AstraZeneca|Cancer Research UK |
June 22 2017 | Phase 1 |
化学情報
| 分子量 | 500.6 | 化学式 | C27H32N8O2 |
| CAS No. | 955365-80-7 | SDF | Download Adavosertib (MK-1775) SDFをダウンロードする |
| Smiles | CC(C)(C1=NC(=CC=C1)N2C3=NC(=NC=C3C(=O)N2CC=C)NC4=CC=C(C=C4)N5CCN(CC5)C)O | ||
| 保管 | |||
|
In vitro |
DMSO : 100 mg/mL ( (199.76 mM)； 吸湿したDMSOは溶解度を減少させます。新しいDMSOをご使用ください。) Water : Insoluble Ethanol : Insoluble |
モル濃度計算器 |
|
in vivo Add solvents to the product individually and in order. |
投与溶液組成計算機 | ||||
実験計算
投与溶液組成計算機(クリア溶液)
ステップ１：実験データを入力してください。（実験操作によるロスを考慮し、動物数を1匹分多くして計算・調製することを推奨します）
mg/kg
g
μL
匹
ステップ２：投与溶媒の組成を入力してください。（ロット毎に適した溶解組成が異なる場合があります。詳細については弊社までお問い合わせください）
% DMSO
%
% Tween 80
% ddH2O
%DMSO
%
計算結果：
投与溶媒濃度： mg/ml;
DMSOストック溶液調製方法： mg 試薬を μL DMSOに溶解する（濃度 mg/mL, 注：濃度が当該ロットのDMSO溶解度を超える場合はご連絡ください。 )
投与溶媒調製方法：Take μL DMSOストック溶液に μL PEG300，を加え、完全溶解後μL Tween 80，を加えて完全溶解させた後 μL ddH2O，を加え完全に溶解させます。
投与溶媒調製方法：μL DMSOストック溶液に μL Corn oil，を加え、完全溶解。
注意：１.ストック溶液に沈殿、混濁などがないことをご確認ください；
２.順番通りに溶剤を加えてください。次のステップに進む前に溶液に沈殿、混濁などがないことを確認してから加えてください。ボルテックス、ソニケーション、水浴加熱など物理的な方法で溶解を早めることは可能です。
技術サポート
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他に質問がある場合は、お気軽にお問い合わせください。
* 必須
よくある質問（FAQ）
質問1:
How to prepare MK1775 methylcellulose solution? and how to prepare methylcellulose itself? Once make the MK1775 methylcellulose solution, how should i keep it?
回答
MK1775 in 0.5% methylcellulose is a suspension or emulsion, and it is ok to treat mice orally. It is recommended to dissolve methylcellulose in saline. It will take some time to dissolve methylcellulose, and you can vortex it for a while. The MK1775 methylcellulose solution can be stored at 4°C for a week.
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