Capivasertib (AZD5363)
中文名称：卡帕塞替尼
Capivasertib (AZD5363)有效抑制Akt(Akt1/Akt2/3)的所有亚型，在无细胞试验中IC50为3 nM/8 nM/8 nM，对P70S6K/PKA也具有相似的抑制效果，而对ROCK1/2抑制活性较低。Phase 2。
Capivasertib (AZD5363) Chemical Structure
CAS: 1143532-39-1
客户使用Selleck的Capivasertib (AZD5363)发表文献127篇
产品质控
批次：
纯度：
99.89%
99.89
常与Capivasertib (AZD5363)一起在实验中被使用的化合物
Capivasertib和Everolimus抑制纯合H2189Y突变细胞的增殖。
Capivasertib和Alpelisib最近被批准与雌激素受体降解剂氟维司群联合用于治疗ER+晚期乳腺癌。
Capivasertib和Enzalutamide在前列腺癌细胞系LNCaP和C4-2中协同减少细胞增殖并诱导细胞周期停滞和凋亡。
Capivasertib联合一线Paclitaxel治疗三阴性乳腺癌(TNBC)可显着延长无进展生存期(PFS)和总生存期(OS)。
Capivasertib和Palbociclib协同抑制管腔雄激素受体(LAR)三阴性乳腺癌(TNBC)细胞的增殖。
Capivasertib (AZD5363)相关产品
| 相关靶点 | Akt1 Akt2 Akt3 | 点击展开 |
|---|---|---|
| 相关化合物库 | 激酶抑制剂库 PI3K/Akt 抑制剂库 凋亡分子化合物库 细胞周期化合物库 NF-κB信号通路库 | 点击展开 |
相关信号通路图
Akt抑制剂选择性比较
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 |
|---|---|---|---|---|---|
| LNCaP | Function Assay | 5 μM | 0-24 h | induces AKTS473 and AKTT308 phosphorylation in a time dependent manner | 23966621 |
| C4-2 | Function Assay | 5 μM | 0-24 h | induces AKTS473 and AKTT308 phosphorylation in a time dependent manner | 23966621 |
| LNCaP | Function Assay | 5 μM | 0-24 h | inhibits phosphorylation of the distal AKT-pathway biomarkers including PRAS40, eIF4E, 4E-BP1, mTOR, and P70 S6 kinase in a time-dependent manner | 23966621 |
| C4-2 | Function Assay | 5 μM | 0-24 h | inhibits phosphorylation of the distal AKT-pathway biomarkers including PRAS40, eIF4E, 4E-BP1, mTOR, and P70 S6 kinase in a time-dependent manner | 23966621 |
| LNCaP | Growth Inhibition Assay | 1-10000 nM | 0-3 d | inhibits cell viability dose dependently | 23966621 |
| C4-2 | Growth Inhibition Assay | 1-10000 nM | 0-3 d | inhibits cell viability dose dependently | 23966621 |
| LNCaP | Growth Inhibition Assay | 100-5000 nM | 72 h | increases the fraction of cells undergoing cell death | 23966621 |
| C4-2 | Growth Inhibition Assay | 100-5000 nM | 72 h | increases the fraction of cells undergoing cell death | 23966621 |
| PC-3 | Function Assay | 0.5/1/10 μM | 48 h | downregulates the phosphorylation of downstream pathway proteins in a dose-dependent manner | 23258740 |
| DU145 | Function Assay | 0.5/1/10 μM | 48 h | downregulates the phosphorylation of downstream pathway proteins in a dose-dependent manner | 23258740 |
| LNCaP | Cell Viability Assay | 0-1000 nM | 0-4 d | reduced LNCaP cell viability in a dose- and time-dependent manner | 23258740 |
| PC-3 | Function Assay | 10 μM | 12 h | induces autophagy | 23258740 |
| PC-9 | Function Assay | 1/5/10 μM | 4/24 h | increases AKT phosphorylation | 24957682 |
| NCI-H522 | Function Assay | 1/5/10 μM | 4/24 h | increases AKT phosphorylation | 24957682 |
| MR49F | Growth Inhibition Assay | 0-5 μM | 48 h | inhibits cell growth in a dose dependent manner | 25151012 |
| MR49C | Growth Inhibition Assay | 0-5 μM | 48 h | inhibits cell growth in a dose dependent manner | 25151012 |
| SKBR3 | Growth Inhibition Assay | 0-1.35 μM | 5 d | enhances the growth inhibition of AZD8931 | 26095475 |
| KPL4 | Growth Inhibition Assay | 0-1.35 μM | 5 d | enhances the growth inhibition of AZD8931 | 26095475 |
| BT474c | Growth Inhibition Assay | 0-1.35 μM | 5 d | enhances the growth inhibition of AZD8931 | 26095475 |
| HCC1954 | Growth Inhibition Assay | 0-1.35 μM | 5 d | enhances the growth inhibition of AZD8931 | 26095475 |
| TamR | Growth Inhibition Assay | 400 nM | 6 d | increased drug sensitivity of 4-OHT and fulvestrant | 26351323 |
| T74D LTED | Growth Inhibition Assay | 100 nM | 6 d | increased drug sensitivity of 4-OHT and fulvestrant | 26351323 |
| ZR75 LTED | Growth Inhibition Assay | 100 nM | 6 d | increased drug sensitivity of 4-OHT and fulvestrant | 26351323 |
| MCF7 LTED | Growth Inhibition Assay | 200 nM | 6 d | increased drug sensitivity of 4-OHT and fulvestrant | 26351323 |
| 1%MCF7 | Growth Inhibition Assay | 400 nM | 6 d | increased drug sensitivity of 4-OHT and fulvestrant | 26351323 |
| T74D | Growth Inhibition Assay | 100 nM | 6 d | increased drug sensitivity of 4-OHT and fulvestrant | 26351323 |
| ZR75 | Growth Inhibition Assay | 100 nM | 6 d | increased drug sensitivity of 4-OHT and fulvestrant | 26351323 |
| MCF7 | Growth Inhibition Assay | 200 nM | 6 d | increased drug sensitivity of 4-OHT and fulvestrant | 26351323 |
| MDA-MB-468 | Function assay | 2 hrs | Inhibition of Akt in human MDA-MB-468 cells assessed as inhibition of GSK3beta phosphorylation after 2 hrs by laser scanning cytometry, IC50 = 0.089 μM. | 23394218 | |
| PTEN-null LNCAP | Function assay | 1 hr | Inhibition of Akt in human PTEN-null LNCAP cells assessed as suppression in PRAS40 phosphorylation after 1 hr by ELISA analysis, IC50 = 0.3368 μM. | 27089211 | |
| HCT116 | Antiproliferative assay | 72 hrs | Antiproliferative activity against human HCT116 cells after 72 hrs by SRB assay, IC50 = 5.2 μM. | 27089211 | |
| OVCAR8 | Antiproliferative assay | 72 hrs | Antiproliferative activity against human OVCAR8 cells after 72 hrs by SRB assay, IC50 = 7.27 μM. | 27089211 | |
| SNU-638 | Growth Inhibition Assay | IC50=4.523 μM | 24088382 | ||
| SNU-1 | Growth Inhibition Assay | IC50=5.258 μM | 24088382 | ||
| SNU-601 | Growth Inhibition Assay | IC50=5.938 μM | 24088382 | ||
| SNU-668 | Growth Inhibition Assay | IC50=6.003 μM | 24088382 | ||
| HS746T | Growth Inhibition Assay | IC50=6.084 μM | 24088382 | ||
| KATO III | Growth Inhibition Assay | IC50=7.267 μM | 24088382 | ||
| SNU-484 | Growth Inhibition Assay | IC50=7.392 μM | 24088382 | ||
| OCUM-1 | Growth Inhibition Assay | IC50=14.515 μM | 24088382 | ||
| SNU-16 | Growth Inhibition Assay | IC50=11.097 μM | 24088382 | ||
| NUGC-3 | Growth Inhibition Assay | IC50=21.873 μM | 24088382 | ||
| AZ521 | Growth Inhibition Assay | IC50=25.448 μM | 24088382 | ||
| SNU-216 | Growth Inhibition Assay | IC50=30 μM | 24088382 | ||
| NUGC-4 | Growth Inhibition Assay | IC50=30 μM | 24088382 | ||
| SNU-5 | Growth Inhibition Assay | IC50=30 μM | 24088382 | ||
| GTL-16 | Growth Inhibition Assay | IC50=30 μM | 24088382 | ||
| MKN74 | Growth Inhibition Assay | IC50=30 μM | 24088382 | ||
| PAMC82 | Growth Inhibition Assay | IC50=30 μM | 24088382 | ||
| SNU-620 | Growth Inhibition Assay | IC50=3.384 μM | 24088382 | ||
| MKN1 | Growth Inhibition Assay | IC50=2.421 μM | 24088382 | ||
| 23132/87 | Growth Inhibition Assay | IC50=1.671 μM | 24088382 | ||
| NCI-N87 | Growth Inhibition Assay | IC50=1.037 μM | 24088382 | ||
| AGS | Growth Inhibition Assay | IC50=0.552 μM | 24088382 | ||
| IM95m | Growth Inhibition Assay | IC50=0.51 μM | 24088382 | ||
| HGC27 | Growth Inhibition Assay | IC50=0.445 μM | 24088382 | ||
| PC-9 | Growth Inhibition Assay | IC50=9.3 (±1.2) μM | 24957682 | ||
| NCI-H522 | Growth Inhibition Assay | IC50=11.3 (±2.7) μM | 24957682 | ||
| LNCaP | Function assay | Inhibition of Akt in PTEN-deficient human LNCaP cells assessed as phosphorylation of GSK3beta, IC50 = 0.06 μM. | 23394218 | ||
| LNCaP | Function assay | Inhibition of Akt in PTEN-deficient human LNCaP cells assessed as phosphorylation of PRAS40, IC50 = 0.22 μM. | 23394218 | ||
| BT474c | Function assay | Inhibition of Akt in human BT474c cells harboring HER2+/PIK3CA double mutant assessed as phosphorylation of PRAS40, IC50 = 0.31 μM. | 23394218 | ||
| MDA-MB-468 | Function assay | Inhibition of Akt in PTEN-deficient human MDA-MB-468 cells assessed as phosphorylation of GSK3beta, IC50 = 0.38 μM. | 23394218 | ||
| MDA-MB-468 | Function assay | Inhibition of Akt in PTEN-deficient human MDA-MB-468 cells assessed as phosphorylation of PRAS40, IC50 = 0.39 μM. | 23394218 | ||
| BT474c | Function assay | Inhibition of Akt in human BT474c cells harboring HER2+/PIK3CA double mutant assessed as phosphorylation of GSK3beta, IC50 = 0.76 μM. | 23394218 | ||
| RT4 | Function assay | Inhibition of PKA in TSC1 deficient human RT4 cells assessed as S6 phosphorylation, IC50 = 1 μM. | 23394218 | ||
| RT4 | Function assay | Inhibition of P70S6K in TSC1 deficient human RT4 cells assessed as S6 phosphorylation, IC50 = 5 μM. | 23394218 | ||
| A673 | qHTS assay | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for A673 cells | 29435139 | ||
| DAOY | qHTS assay | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for DAOY cells | 29435139 | ||
| Saos-2 | qHTS assay | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for Saos-2 cells | 29435139 | ||
| SK-N-SH | qHTS assay | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for SK-N-SH cells | 29435139 | ||
| NB1643 | qHTS assay | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for NB1643 cells | 29435139 | ||
| MG 63 (6-TG R) | qHTS assay | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for MG 63 (6-TG R) cells | 29435139 | ||
| Rh41 | qHTS assay | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for Rh41 cells | 29435139 | ||
| SK-N-MC | qHTS assay | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for SK-N-MC cells | 29435139 | ||
| NB-EBc1 | qHTS assay | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for NB-EBc1 cells | 29435139 | ||
| LAN-5 | qHTS assay | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for LAN-5 cells | 29435139 | ||
| Rh18 | qHTS assay | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for Rh18 cells | 29435139 | ||
| 点击查看更多细胞系数据 | |||||
生物活性
| 产品描述 | Capivasertib (AZD5363)有效抑制Akt(Akt1/Akt2/3)的所有亚型，在无细胞试验中IC50为3 nM/8 nM/8 nM，对P70S6K/PKA也具有相似的抑制效果，而对ROCK1/2抑制活性较低。Phase 2。 | ||||||||
|---|---|---|---|---|---|---|---|---|---|
| 特性 | AZD5363具有良好的临床前期耐受性，和AKT抑制剂的药效学特性，且不同于其他AKT抑制剂具有卓越的特性，已经进入临床开发阶段。[2] | ||||||||
| 靶点 |
|
| 体外研究(In Vitro) | ||||
| 体外研究活性 | AZD5363是有效的Akt抑制剂，抑制Akt1, Akt2 和 Akt3时，IC50分别为3 nM, 8 nM 和 8 nM。PIK3CA突变的激活，肿瘤抑制基因PTEN的丢失或失活，或HER2的扩增，都与AZD5363有着显著的关系。此外，还可以看出细胞系的RAS突变状态与抗AZD5363之间的相关性。[1]AZD5363在细胞中抑制AKT底物的磷酸化，效价约为0.3〜0.8μM。AZD5363抑制182种实体和血液肿瘤细胞系中的41种细胞增殖，效价为< 3 μM。[2] | |||
|---|---|---|---|---|
| 激酶实验 | Caliper Off-Chip Incubation迁移率变动分析 | |||
| 通过 Caliper Off-Chip Incubation迁移率变动分析测评AZD5363和其他化合物抑制AKT1, AKT2, 和 AKT3活性的能力。活跃的重组AKT1，AKT2，或AKT3与5-FAM标记的定制合成的肽底物，及浓度不断增加的抑制剂温育。最终反应包含1 到 3 nM AKT1, AKT2, 或AKT3 酶; 1.5 mM 肽底物; AKT亚型的ATP为Km; 10 mM MgCl2, 4 mM DTT, 100 mM HEPES, 及0.015% Brij-35。反应在室温下温育1小时，然后加入含100 mM HEPES, 0.015% Brij-35 溶液, 0.1% 涂层试剂， 40 mM EDTA, 和5% DMSO的buffer终止反应。使用Caliper LC3000分析实验板，进行肽底物的分离，对磷酸化的产物进行电泳和激光诱导荧光的检测和量化。 | ||||
| 细胞实验 | 细胞系 | 182种实体和血液肿瘤细胞系 | ||
| 浓度 | 0.003 μM-30 μM | |||
| 孵育时间 | 72 小时 | |||
| 方法 | 通过MTS和Sytox Green2种方法测定细胞增殖实验。细胞接种在96孔板中，在37°C下,含 5% CO2的环境中温育过夜。使用浓度为30 到 0.003μM的 AZD5363处理细胞72小时。对于MTS端点，通过CellTiter AQueous非放射性细胞增殖检测试剂测量细胞增殖。对于Sytox Green 端点，在TBS-EDTA buffer 中稀释的Sytox Green核酸染料加到细胞中（终浓度为0.13μM），使用Acumen Explorer测定死亡细胞数。通过加入Saponin（终浓度0.03％，在TBS-EDTA buffer中稀释）使细胞具有渗透性，温育过夜，并测量总细胞数。MTS 和Sytox Green 端点都是给药前测量，使用吸光度读数（MTS）或活细胞计数测定将实验组细胞的生长降低到未处理组细胞的一半所需要的浓度值。 | |||
| 实验图片 | 检测方法 | 检测指标 | 实验图片 | PMID |
| Western blot | pAKT / AKT / pGSK3β / GSK3β HER3 / pHER3 / HER2 / pHER2 / pPRAS40 / pS6 / p-4EBP1 / pFOXO / pERK / PARP / Cleaved PARP |
|
26998062 | |
| Immunofluorescence | p-Chk2 / γ-H2AX |
|
29879757 | |
| Growth inhibition assay | Cell viability |
|
29879757 | |
| 体内研究(In Vivo) | ||
| 体内研究活性 | AZD5363按100, 300 mg/kg剂量口服给药裸鼠，降低BT474c移植瘤中PRAS40, GSK3β,和 S6的磷酸化，这种作用具有剂量和时间依赖性，也可逆性地增加血糖浓度，且降低U87-MG移植瘤中2[18F]氟-2-脱氧-d-葡萄糖(18F-FDG)的摄取，这种作用存在剂量依赖性。AZD5363按130, 200, 和300 mg/kg剂量慢性口服给药从各种肿瘤类型衍生的移植瘤，包括抗Trastuzumab的HER2+乳腺癌模型，抑制移植瘤的生长，这种作用存在剂量依赖性。AZD5363在乳腺癌移植瘤中也显著增强 Docetaxel, Lapatinib, 和 Trastuzumab的抗肿瘤活性。[2] | |
|---|---|---|
| 动物实验 | Animal Models | 携带 BT474c, U87MG, KPL-4, HCC-1187 移植瘤的雌性裸鼠和雄性SCID小鼠 |
| Dosages | 130 mg/Kg-300 mg/Kg | |
| Administration | 口服处理 | |
| NCT Number | Recruitment | Conditions | Sponsor/Collaborators | Start Date | Phases |
|---|---|---|---|---|---|
| NCT03310541 | Completed | Breast Cancer|Prostate Cancer|Advanced Solid Tumors |
Memorial Sloan Kettering Cancer Center |
October 11 2017 | Phase 1 |
| NCT01992952 | Active not recruiting | Estrogen Receptor Positive Breast Cancer |
Velindre NHS Trust|AstraZeneca|Cenduit LLC|Covance|Cardiff and Vale University Health Board |
May 2014 | Phase 1|Phase 2 |
| NCT02338622 | Completed | Advanced Cancer |
Royal Marsden NHS Foundation Trust|Institute of Cancer Research United Kingdom|AstraZeneca |
March 31 2014 | Phase 1 |
| NCT02121639 | Completed | Prostate Cancer |
University Hospital Southampton NHS Foundation Trust|AstraZeneca|Cancer Research UK |
January 29 2014 | Phase 1|Phase 2 |
| NCT02077569 | Completed | Invasive Breast Cancer |
University of Nottingham|AstraZeneca|Cancer Research UK|National Cancer Research Network |
January 2014 | Phase 2 |
| NCT01692262 | Completed | Metastatic Castrate-Resistant Prostate Cancer (mCRPC)|Efficacy|Safety and Tolerability|Pharmacokinetics|Pharmacodynamics|Tumour Response. |
AstraZeneca |
November 2012 | Phase 1 |
化学信息&溶解度
| 分子量 | 428.92 | 分子式 | C21H25ClN6O2 |
| CAS号 | 1143532-39-1 | SDF | Download Capivasertib (AZD5363) SDF |
| Smiles | C1CN(CCC1(C(=O)NC(CCO)C2=CC=C(C=C2)Cl)N)C3=NC=NC4=C3C=CN4 | ||
| 储存条件(自收到货起) | |||
|
体外溶解度 |
DMSO : 86 mg/mL ( (200.5 mM)； DMSO吸湿会降低化合物溶解度，请使用新开封DMSO) Ethanol : 30 mg/mL Water : Insoluble |
摩尔浓度计算器 |
|
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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