Adavosertib (MK-1775)
别名: AZD1775
Adavosertib (MK-1775, AZD1775)是一种有效的，高选择性Wee1抑制剂，无细胞试验中IC50为5.2 nM；阻碍G2期DNA损伤检验点。Phase 2。
Adavosertib (MK-1775) Chemical Structure
CAS: 955365-80-7
产品质控
批次：
纯度：
99.99%
99.99
Adavosertib (MK-1775)相关产品
| 相关产品 | PD0166285 | 点击展开 |
|---|---|---|
| 相关化合物库 | 激酶抑制剂库 PI3K/Akt 抑制剂库 MAPK抑制剂库 DNA损伤/ DNA修复化合物库 细胞周期化合物库 | 点击展开 |
相关信号通路图
细胞实验数据示例
| 细胞系 | 实验类型 | 给药浓度 | 孵育时间 | 活性描述 | 文献信息 |
|---|---|---|---|---|---|
| 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 | ||
| 点击查看更多细胞系数据 | |||||
生物活性
| 产品描述 | Adavosertib (MK-1775, AZD1775)是一种有效的，高选择性Wee1抑制剂，无细胞试验中IC50为5.2 nM；阻碍G2期DNA损伤检验点。Phase 2。 | ||
|---|---|---|---|
| 特性 | 首个报道的 Wee1抑制剂。 | ||
| 靶点 |
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| 体外研究(In Vitro) | ||||
| 体外研究活性 | MK-1775以ATP竞争的方式抑制Wee1激酶。与作用于Wee1相比，MK-1775对Yes的效能低2-到3-倍，IC50为14 nM，对7种其他激酶的效能低10倍，1 μM浓度下抑制率>80%，比对人Myt 1选择性高100倍以上，并抑制周期蛋白依赖性激酶1 (CDC2) 在可选择位点(Thr14) 的磷酸化作用。通过阻断负荷突变型p53的WiDr细胞中Wee1活性，废止DNA损伤检控点，MK-1775治疗抑制Tyr15 (CDC2Y15)位点的CDC2基础磷酸化作用，EC50为49 nM，并剂量依赖性抑制诱导的CDC2磷酸化和细胞周期阻滞，EC50分别为82 nM和81 nM，180 nM 和163 nM，以及159 nM 和 160 nM。30-100 nM 的MK-1775单独治疗在WiDr 和 H1299细胞中没有显著的抗增殖作用，而300 nM的MK-1775足以抑制>80%的Wee1，表现出温和但显著的抗增殖作用，在WiDr和H1299细胞中抑制率分别为34.1%和28.4%。[1] |
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|---|---|---|---|---|
| 激酶实验 | 体外激酶试验 | |||
| 使用重组人Wee1。激酶反应使用10 μM ATP，1.0 μCi of [γ-33P]ATP，和2.5 μg poly(Lys, Tyr)作为底物，在逐渐增加浓度的MK-1775存在下，在30°C环境中进行30分钟。整合到底物的放射性被捕获到MultiScreen-PH平板，在液体闪烁计数器上计数。 | ||||
| 细胞实验 | 细胞系 | WiDr，NCI-H1299，TOV21G，和 HeLa细胞 | ||
| 浓度 | 在DMSO中溶解，终浓度为~10 μM | |||
| 孵育时间 | 24小时 | |||
| 方法 | 细胞处理24小时，然后用MK-1775再处理24小时。细胞活性使用SpectraMax通过WST-8试剂盒测定。细胞内caspase-3/7活性使用Caspase-3/7 Glo试剂盒测定。 |
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| 实验图片 | 检测方法 | 检测指标 | 实验图片 | 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 | |
| 体内研究(In Vivo) | ||
| 体内研究活性 | MK-1775(~20 mg/kg)单独治疗对WiDr异种移植物表现出最小的抗肿瘤作用，在大鼠体内第3天时T/C为69%。在裸鼠HeLa-luc和TOV21G-shp53异种移植模型中，MK-1775单独的抗肿瘤效能是温和的。[1] |
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|---|---|---|
| 动物实验 | Animal Models | 负荷WiDr，HeLa-luc，或TOV21G-shp53肿瘤的免疫缺陷裸鼠(F344/NJcl-rnu) |
| Dosages | ~20 mg/kg/day | |
| Administration | 口服 | |
| 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 |
化学信息&溶解度
| 分子量 | 500.6 | 分子式 | C27H32N8O2 |
| CAS号 | 955365-80-7 | SDF | Download Adavosertib (MK-1775) SDF |
| Smiles | CC(C)(C1=NC(=CC=C1)N2C3=NC(=NC=C3C(=O)N2CC=C)NC4=CC=C(C=C4)N5CCN(CC5)C)O | ||
| 储存条件(自收到货起) | |||
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体外溶解度 |
DMSO : 100 mg/mL ( (199.76 mM) ；DMSO吸湿会降低化合物溶解度，请使用新开封DMSO) Water : Insoluble Ethanol : Insoluble |
摩尔浓度计算器 |
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体内溶解度 现配现用，请按从左到右的顺序依次添加，澄清后再加入下一溶剂 |
动物体内配方计算器 | ||||
实验计算
动物体内配方计算器（澄清溶液）
第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量）
mg/kg
g
μL
只
第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系Selleck为您提供正确的澄清溶液配方）
% DMSO
%
% Tween 80
% ddH2O
%DMSO
%
计算结果：
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于μL DMSO溶液（母液浓度mg/mL，注：如该浓度超过该批次药物DMSO溶解度，请先联系Selleck）；
体内配方配制方法：取μL DMSO母液，加入μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入μL ddH2O，混匀澄清。
体内配方配制方法：取μL DMSO母液，加入μL Corn oil，混匀澄清。
注意：1. 首先保证母液是澄清的；
2.一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
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常见问题及建议解决方法
问题 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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