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

Capivasertib (AZD5363) Chemical Structure

CAS: 1143532-39-1

规格 价格 库存 购买数量
10mM (1mL in DMSO) 1926.33 现货
5mg 1216.65 现货
25mg 3865.98 现货
100mg 9582.3 现货
1g 20229.3 现货
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常与Capivasertib (AZD5363)一起在实验中被使用的化合物

Everolimus


Capivasertib和Everolimus抑制纯合H2189Y突变细胞的增殖。

Wu X, et al. Cancer Biol Ther. 2018 Jul 3;19(7):584-589.

Alpelisib (BYL719)


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。

Alves CL, et al. Int J Mol Sci. 2023 Feb 24;24(5):4522.

Enzalutamide


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。

Toren P, et al. Eur Urol. 2015 Jun;67(6):986-990.

Paclitaxel


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)。

Schmid P, et al. J Clin Oncol. 2020 Feb 10;38(5):423-433.

Palbociclib


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。

Kim GM, et al. Cancer Res (2022) 82 (4_Supplement): PD3-07.

Capivasertib (AZD5363)相关产品

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
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
Akt1 [1]
(Cell-free assay)
Akt2 [1]
(Cell-free assay)
Akt3 [1]
(Cell-free assay)
ROCK2 [1]
(Cell-free assay)
3 nM 8 nM 8 nM 56 nM
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,抑制移植瘤的生长,这种作用存在剂量依赖性。

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
批次:

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 (69.94 mM)

Water : Insoluble

摩尔浓度计算器

体内溶解度
批次:

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

摩尔浓度计算器

质量 浓度 体积 分子量

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

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,: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: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: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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