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Capivasertib (AZD5363)

中文名稱(chēng)：卡帕塞替尼

Capivasertib (AZD5363)有效抑制Akt(Akt1/Akt2/3)的所有亞型，在無(wú)細(xì)胞試驗(yàn)中IC50為3 nM/8 nM/8 nM，對(duì)P70S6K/PKA也具有相似的抑制效果，而對(duì)ROCK1/2抑制活性較低。Phase 2。

Capivasertib (AZD5363) Chemical Structure

Capivasertib (AZD5363) Chemical Structure

CAS: 1143532-39-1

規(guī)格 價(jià)格 庫(kù)存 購(gòu)買(mǎi)數(shù)量
10mM (1mL in DMSO) 1926.33 現(xiàn)貨
5mg 1216.65 現(xiàn)貨
25mg 3865.98 現(xiàn)貨
100mg 9582.3 現(xiàn)貨
1g 20229.3 現(xiàn)貨
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常與Capivasertib (AZD5363)一起在實(shí)驗(yàn)中被使用的化合物

Everolimus

Capivasertib和Everolimus抑制純合H2189Y突變細(xì)胞的增殖。

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

Alpelisib (BYL719)

Capivasertib和Alpelisib最近被批準(zhǔn)與雌激素受體降解劑氟維司群聯(lián)合用于治療ER+晚期乳腺癌。

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

Enzalutamide

Capivasertib和Enzalutamide在前列腺癌細(xì)胞系LNCaP和C4-2中協(xié)同減少細(xì)胞增殖并誘導(dǎo)細(xì)胞周期停滯和凋亡。

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

Paclitaxel

Capivasertib聯(lián)合一線(xiàn)Paclitaxel治療三陰性乳腺癌(TNBC)可顯著延長(zhǎng)無(wú)進(jìn)展生存期(PFS)和總生存期(OS)。

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

Palbociclib

Capivasertib和Palbociclib協(xié)同抑制管腔雄激素受體(LAR)三陰性乳腺癌(TNBC)細(xì)胞的增殖。

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

Capivasertib (AZD5363)相關(guān)產(chǎn)品

相關(guān)信號(hào)通路圖

Akt Signaling Pathways

Akt信號(hào)通路圖

細(xì)胞實(shí)驗(yàn)數(shù)據(jù)示例

細(xì)胞系 實(shí)驗(yàn)類(lèi)型 給藥濃度 孵育時(shí)間 活性描述 文獻(xiàn)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
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生物活性

產(chǎn)品描述 Capivasertib (AZD5363)有效抑制Akt(Akt1/Akt2/3)的所有亞型，在無(wú)細(xì)胞試驗(yàn)中IC50為3 nM/8 nM/8 nM，對(duì)P70S6K/PKA也具有相似的抑制效果，而對(duì)ROCK1/2抑制活性較低。Phase 2。
特性 AZD5363具有良好的臨床前期耐受性，和AKT抑制劑的藥效學(xué)特性，且不同于其他AKT抑制劑具有卓越的特性，已經(jīng)進(jìn)入臨床開(kāi)發(fā)階段。[2]
靶點(diǎn)
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
體外研究(In Vitro)
體外研究活性

AZD5363是有效的Akt抑制劑，抑制Akt1, Akt2 和 Akt3時(shí)，IC50分別為3 nM, 8 nM 和 8 nM。PIK3CA突變的激活，腫瘤抑制基因PTEN的丟失或失活，或HER2的擴(kuò)增，都與AZD5363有著顯著的關(guān)系。此外，還可以看出細(xì)胞系的RAS突變狀態(tài)與抗AZD5363之間的相關(guān)性。[1]AZD5363在細(xì)胞中抑制AKT底物的磷酸化，效價(jià)約為0.3?0.8μM。AZD5363抑制182種實(shí)體和血液腫瘤細(xì)胞系中的41種細(xì)胞增殖，效價(jià)為< 3 μM。[2]
激酶實(shí)驗(yàn) Caliper Off-Chip Incubation遷移率變動(dòng)分析
通過(guò) Caliper Off-Chip Incubation遷移率變動(dòng)分析測(cè)評(píng)AZD5363和其他化合物抑制AKT1, AKT2, 和 AKT3活性的能力?；钴S的重組AKT1，AKT2，或AKT3與5-FAM標(biāo)記的定制合成的肽底物，及濃度不斷增加的抑制劑溫育。最終反應(yīng)包含1 到 3 nM AKT1, AKT2, 或AKT3 酶; 1.5 mM 肽底物; AKT亞型的ATP為Km; 10 mM MgCl2, 4 mM DTT, 100 mM HEPES, 及0.015% Brij-35。反應(yīng)在室溫下溫育1小時(shí)，然后加入含100 mM HEPES, 0.015% Brij-35 溶液, 0.1% 涂層試劑， 40 mM EDTA, 和5% DMSO的buffer終止反應(yīng)。使用Caliper LC3000分析實(shí)驗(yàn)板，進(jìn)行肽底物的分離，對(duì)磷酸化的產(chǎn)物進(jìn)行電泳和激光誘導(dǎo)熒光的檢測(cè)和量化。
細(xì)胞實(shí)驗(yàn) 細(xì)胞系 182種實(shí)體和血液腫瘤細(xì)胞系
濃度 0.003 μM-30 μM
孵育時(shí)間 72 小時(shí)
方法

通過(guò)MTS和Sytox Green2種方法測(cè)定細(xì)胞增殖實(shí)驗(yàn)。細(xì)胞接種在96孔板中，在37°C下,含 5% CO2的環(huán)境中溫育過(guò)夜。使用濃度為30 到 0.003μM的 AZD5363處理細(xì)胞72小時(shí)。對(duì)于MTS端點(diǎn)，通過(guò)CellTiter AQueous非放射性細(xì)胞增殖檢測(cè)試劑測(cè)量細(xì)胞增殖。對(duì)于Sytox Green 端點(diǎn)，在TBS-EDTA buffer 中稀釋的Sytox Green核酸染料加到細(xì)胞中（終濃度為0.13μM），使用Acumen Explorer測(cè)定死亡細(xì)胞數(shù)。通過(guò)加入Saponin（終濃度0.03％，在TBS-EDTA buffer中稀釋?zhuān)┦辜?xì)胞具有滲透性，溫育過(guò)夜，并測(cè)量總細(xì)胞數(shù)。MTS 和Sytox Green 端點(diǎn)都是給藥前測(cè)量，使用吸光度讀數(shù)（MTS）或活細(xì)胞計(jì)數(shù)測(cè)定將實(shí)驗(yàn)組細(xì)胞的生長(zhǎng)降低到未處理組細(xì)胞的一半所需要的濃度值。
實(shí)驗(yàn)圖片 檢測(cè)方法 檢測(cè)指標(biāo) 實(shí)驗(yàn)圖片 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
體內(nèi)研究(In Vivo)
體內(nèi)研究活性

AZD5363按100, 300 mg/kg劑量口服給藥裸鼠，降低BT474c移植瘤中PRAS40, GSK3β,和 S6的磷酸化，這種作用具有劑量和時(shí)間依賴(lài)性，也可逆性地增加血糖濃度，且降低U87-MG移植瘤中2[18F]氟-2-脫氧-d-葡萄糖(18F-FDG)的攝取，這種作用存在劑量依賴(lài)性。AZD5363按130, 200, 和300 mg/kg劑量慢性口服給藥從各種腫瘤類(lèi)型衍生的移植瘤，抑制移植瘤的生長(zhǎng)，這種作用存在劑量依賴(lài)性。
動(dòng)物實(shí)驗(yàn) Animal Models 攜帶 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 口服處理
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

化學(xué)信息&溶解度

分子量 428.92 分子式

C21H25ClN6O2
CAS號(hào) 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
儲(chǔ)存條件(自收到貨起)

體外溶解度
批次：

DMSO : 86 mg/mL ( (200.5 mM) ；DMSO吸濕會(huì)降低化合物溶解度，請(qǐng)使用新開(kāi)封DMSO)

Ethanol : 30 mg/mL (69.94 mM)

Water : Insoluble

摩爾濃度計(jì)算器

體內(nèi)溶解度
批次：

現(xiàn)配現(xiàn)用，請(qǐng)按從左到右的順序依次添加，澄清后再加入下一溶劑

 動(dòng)物體內(nèi)配方計(jì)算器

實(shí)驗(yàn)計(jì)算

摩爾濃度計(jì)算器

質(zhì)量 濃度 體積 分子量

動(dòng)物體內(nèi)配方計(jì)算器（澄清溶液）

第一步：請(qǐng)輸入基本實(shí)驗(yàn)信息（考慮到實(shí)驗(yàn)過(guò)程中的損耗，建議多配一只動(dòng)物的藥量）

mg/kg g μL 只

第二步：請(qǐng)輸入動(dòng)物體內(nèi)配方組成（配方適用于不溶于水的藥物；不同批次藥物配方比例不同，請(qǐng)聯(lián)系Selleck為您提供正確的澄清溶液配方）

% DMSO % % Tween 80 % ddH2O
%DMSO %

計(jì)算結(jié)果：

工作液濃度： mg/ml；

DMSO母液配制方法： mg 藥物溶于μL DMSO溶液（母液濃度mg/mL，注：如該濃度超過(guò)該批次藥物DMSO溶解度，請(qǐng)先聯(lián)系Selleck）；

體內(nèi)配方配制方法：取μL DMSO母液，加入μL PEG300，混勻澄清后加入μL Tween 80，混勻澄清后加入μL ddH2O，混勻澄清。

體內(nèi)配方配制方法：取μL DMSO母液，加入μL Corn oil，混勻澄清。

注意：1. 首先保證母液是澄清的；
2.一定要按照順序依次將溶劑加入，進(jìn)行下一步操作之前必須保證上一步操作得到的是澄清的溶液，可采用渦旋、超聲或水浴加熱等物理方法助溶。

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