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Capivasertib (AZD5363)
中文名稱：卡帕塞替尼
Capivasertib (AZD5363)有效抑制Akt(Akt1/Akt2/3)的所有亞型，在無細胞試驗中IC50為3 nM/8 nM/8 nM，對P70S6K/PKA也具有相似的抑制效果，而對ROCK1/2抑制活性較低。Phase 2。
Capivasertib (AZD5363) Chemical Structure
CAS: 1143532-39-1
產(chǎn)品質控
批次：
純度：
99.89%
99.89
常與Capivasertib (AZD5363)一起在實驗中被使用的化合物
Capivasertib和Everolimus抑制純合H2189Y突變細胞的增殖。
Capivasertib和Alpelisib最近被批準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。
Capivasertib和Enzalutamide在前列腺癌細胞系LNCaP和C4-2中協(xié)同減少細胞增殖并誘導細胞周期停滯和凋亡。
Capivasertib聯(lián)合一線Paclitaxel治療三陰性乳腺癌(TNBC)可顯著延長無進展生存期(PFS)和總生存期(OS)。
Capivasertib和Palbociclib協(xié)同抑制管腔雄激素受體(LAR)三陰性乳腺癌(TNBC)細胞的增殖。
Capivasertib (AZD5363)相關產(chǎn)品
相關信號通路圖
細胞實驗數(shù)據(jù)示例
| 細胞系 | 實驗類型 | 給藥濃度 | 孵育時間 | 活性描述 | 文獻信息 |
|---|---|---|---|---|---|
| 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 | ||
| 點擊查看更多細胞系數(shù)據(jù) | |||||
生物活性
| 產(chǎn)品描述 | Capivasertib (AZD5363)有效抑制Akt(Akt1/Akt2/3)的所有亞型，在無細胞試驗中IC50為3 nM/8 nM/8 nM，對P70S6K/PKA也具有相似的抑制效果，而對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抑制劑的藥效學特性，且不同于其他AKT抑制劑具有卓越的特性，已經(jīng)進入臨床開發(fā)階段。[2] | ||||||||
| 靶點 |
|
| 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，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的擴增，都與AZD5363有著顯著的關系。此外，還可以看出細胞系的RAS突變狀態(tài)與抗AZD5363之間的相關性。[1]AZD5363在細胞中抑制AKT底物的磷酸化，效價約為0.3?0.8μM。AZD5363抑制182種實體和血液腫瘤細胞系中的41種細胞增殖，效價為< 3 μM。[2] |
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|---|---|---|---|---|
| 激酶實驗 | Caliper Off-Chip Incubation遷移率變動分析 | |||
| 通過 Caliper Off-Chip Incubation遷移率變動分析測評AZD5363和其他化合物抑制AKT1, AKT2, 和 AKT3活性的能力。活躍的重組AKT1，AKT2，或AKT3與5-FAM標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。反應在室溫下溫育1小時，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。使用Caliper LC3000分析實驗板，進行肽底物的分離，對磷酸化的產(chǎn)物進行電泳和激光誘導熒光的檢測和量化。 | ||||
| 細胞實驗 | 細胞系 | 182種實體和血液腫瘤細胞系 | ||
| 濃度 | 0.003 μM-30 μM | |||
| 孵育時間 | 72 小時 | |||
| 方法 | 通過MTS和Sytox Green2種方法測定細胞增殖實驗。細胞接種在96孔板中，在37°C下,含 5% CO2的環(huán)境中溫育過夜。使用濃度為30 到 0.003μM的 AZD5363處理細胞72小時。對于MTS端點，通過CellTiter AQueous非放射性細胞增殖檢測試劑測量細胞增殖。對于Sytox Green 端點，在TBS-EDTA buffer 中稀釋的Sytox Green核酸染料加到細胞中（終濃度為0.13μM），使用Acumen Explorer測定死亡細胞數(shù)。通過加入Saponin（終濃度0.03％，在TBS-EDTA buffer中稀釋）使細胞具有滲透性，溫育過夜，并測量總細胞數(shù)。MTS 和Sytox Green 端點都是給藥前測量，使用吸光度讀數(shù)（MTS）或活細胞計數(shù)測定將實驗組細胞的生長降低到未處理組細胞的一半所需要的濃度值。 |
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| 實驗圖片 | 檢測方法 | 檢測指標 | 實驗圖片 | 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 | |
| 體內研究(In Vivo) | ||
| 體內研究活性 | 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間依賴性，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性。AZD5363按130, 200, 和300 mg/kg劑量慢性口服給藥從各種腫瘤類型衍生的移植瘤，抑制移植瘤的生長，這種作用存在劑量依賴性。 |
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|---|---|---|
| 動物實驗 | 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 |
化學信息&溶解度
| 分子量 | 428.92 | 分子式 | C21H25ClN6O2 |
| CAS號 | 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 | ||
| 儲存條件(自收到貨起) | |||
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體外溶解度 |
DMSO : 86 mg/mL ( (200.5 mM) ；DMSO吸濕會降低化合物溶解度，請使用新開封DMSO) Ethanol : 30 mg/mL (69.94 mM) Water : Insoluble |
摩爾濃度計算器 |
|
體內溶解配方 現(xiàn)配現(xiàn)用，請按從左到右的順序依次添加，澄清后再加入下一溶劑 |
動物體內配方計算器 | |||||
實驗計算
動物體內配方計算器（澄清溶液）
第一步：請輸入基本實驗信息（考慮到實驗過程中的損耗，建議多配一只動物的藥量）
mg/kg
g
μL
只
第二步：請輸入動物體內配方組成（配方適用于不溶于水的藥物；不同批次藥物配方比例不同，請聯(lián)系Selleck為您提供正確的澄清溶液配方）
% DMSO
%
% Tween 80
% ddH2O
%DMSO
%
計算結果：
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：如該濃度超過該批次藥物DMSO溶解度，請先聯(lián)系Selleck）；
體內配方配制方法：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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