Home PI3K/Akt/mTOR Akt inhibitor AZD5363 (Capivasertib)

연구용

AZD5363 (Capivasertib) Akt inhibitor

제품 번호: S8019

Capivasertib (AZD5363) potently inhibits all isoforms of Akt(Akt1/Akt2/Akt3) with IC50 of 3 nM/8 nM/8 nM in cell-free assays, similar to P70S6K/PKA and lower activity towards ROCK1/2. Phase 2.
AZD5363 (Capivasertib) Akt inhibitor Chemical Structure

화학 구조

분자량: 428.92

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품질 관리 (Quality Control)

배치: 순도: 99.60%
99.60

세포 배양, 처리 및 작업 농도
(Cell Culture, Treatment & Working Concentration)

세포주 분석 유형 농도 배양 시간 제형 활성 설명 PMID
PC-3  Function Assay 10 μM 12 h induces autophagy 23258740
LNCaP Cell Viability Assay 0-1000 nM 0-4 d reduced LNCaP cell viability in a dose- and time-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
PC-3 Function Assay 0.5/1/10 μM 48 h downregulates the phosphorylation of downstream pathway proteins in a dose-dependent manner 23258740
C4-2  Growth Inhibition Assay 100-5000 nM 72 h increases the fraction of cells undergoing cell death 23966621
LNCaP Growth Inhibition Assay 100-5000 nM 72 h increases the fraction of cells undergoing cell death 23966621
C4-2  Growth Inhibition Assay 1-10000 nM 0-3 d inhibits cell viability dose dependently 23966621
LNCaP Growth Inhibition Assay 1-10000 nM 0-3 d inhibits cell viability dose dependently 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 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 induces AKTS473 and AKTT308 phosphorylation in a time dependent manner 23966621
LNCaP Function Assay 5 μM 0-24 h induces AKTS473 and AKTT308 phosphorylation in a time dependent manner 23966621
PAMC82 Growth Inhibition Assay IC50=30 μM 24088382
MKN74 Growth Inhibition Assay IC50=30 μM 24088382
GTL-16 Growth Inhibition Assay IC50=30 μM 24088382
SNU-5 Growth Inhibition Assay IC50=30 μM 24088382
NUGC-4 Growth Inhibition Assay IC50=30 μM 24088382
SNU-216 Growth Inhibition Assay IC50=30 μM 24088382
AZ521 Growth Inhibition Assay IC50=25.448 μM 24088382
NUGC-3 Growth Inhibition Assay IC50=21.873 μM 24088382
OCUM-1 Growth Inhibition Assay IC50=14.515 μM 24088382
SNU-16 Growth Inhibition Assay IC50=11.097 μM 24088382
SNU-484 Growth Inhibition Assay IC50=7.392 μM 24088382
KATO III Growth Inhibition Assay IC50=7.267 μM 24088382
HS746T Growth Inhibition Assay IC50=6.084 μM 24088382
SNU-668 Growth Inhibition Assay IC50=6.003 μM 24088382
SNU-601 Growth Inhibition Assay IC50=5.938 μM 24088382
SNU-1 Growth Inhibition Assay IC50=5.258 μM 24088382
SNU-638 Growth Inhibition Assay IC50=4.523 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 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
PC-9 Growth Inhibition Assay IC50=9.3 (±1.2) μM 24957682
NCI-H522 Growth Inhibition Assay IC50=11.3 (±2.7) μM 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
LNCaP Function assay Inhibition of Akt in PTEN-deficient human LNCaP cells assessed as phosphorylation of GSK3beta, IC50 = 0.06 μM. 23394218
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
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
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
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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화학 정보, 보관 및 안정성 (Chemical Information, Storage & Stability)

분자량 428.92 화학식

C21H25ClN6O2

 보관 (수령일로부터)
CAS 번호 1143532-39-1 SDF 다운로드 원액 보관

동의어 N/A Smiles C1CN(CCC1(C(=O)NC(CCO)C2=CC=C(C=C2)Cl)N)C3=NC=NC4=C3C=CN4

용해도 (Solubility)

In vitro
배치:

DMSO : 86 mg/mL (200.5 mM)
(수분으로 오염된 DMSO는 용해도를 감소시킬 수 있습니다. 신선하고 무수 DMSO를 사용하십시오.)

Ethanol : 20 mg/mL

Water : Insoluble

몰농도 계산기

질량 농도 부피 분자량
희석 계산기 분자량 계산기

In vivo
배치:

생체 내 제형 계산기 (투명한 용액)

1단계: 아래 정보 입력 (권장: 실험 중 손실을 고려하여 추가 동물 포함)

mg/kg g μL

2단계: 생체 내 제형 입력 (이것은 계산기일 뿐 제형이 아닙니다. 용해도 섹션에 생체 내 제형이 없는 경우 먼저 당사에 문의하십시오.)

% DMSO % % Tween 80 % ddH2O
%DMSO %

계산 결과:

작업 농도: mg/ml;

DMSO 원액 준비 방법: mg 약물 사전 용해 μL DMSO ( 원액 농도 mg/mL, 농도가 해당 약물 배치의 DMSO 용해도를 초과하는 경우 먼저 당사에 문의하십시오. )

생체 내 제형 준비 방법: 취하다 μL DMSO 원액, 다음 추가μL PEG300, 혼합하고 투명하게 한 다음 추가μL Tween 80, 혼합하고 투명하게 한 다음 추가 μL ddH2O, 혼합하고 투명하게 합니다.

생체 내 제형 준비 방법: 취하다 μL DMSO 원액, 다음 추가 μL 옥수수 기름, 혼합하고 투명하게 합니다.

참고: 1. 다음 용매를 추가하기 전에 액체가 투명한지 확인하십시오.
2. 용매를 순서대로 추가해야 합니다. 다음 용매를 추가하기 전에 이전 추가에서 얻은 용액이 투명한 용액인지 확인해야 합니다. 와동, 초음파 또는 뜨거운 물 중탕과 같은 물리적 방법을 사용하여 용해를 도울 수 있습니다.

작용 메커니즘 (Mechanism of Action)

특징
Moderate preclinical tolerability, and PD characteristics of an AKT inhibitor. Distinct profile from other AKT inhibitors in clinical development.
Targets/IC50/Ki
Akt1
(Cell-free assay)
3 nM
Akt2
(Cell-free assay)
8 nM
Akt3
(Cell-free assay)
8 nM
ROCK2
(Cell-free assay)
56 nM
시험관 내(In vitro)

Capivasertib (AZD5363) is a potent Akt inhibitor with IC50 of 3 nM, 8 nM and 8 nM for Akt1, Akt2 and Akt3, respectively. It inhibits phosphorylation of AKT substrates in cells with a potency of approximately 0.3 to 0.8 μM. This compound inhibits the proliferation of 41 of 182 solid and hematologic tumor cell lines with a potency of < 3 μM. Activating mutations in PIK3CA, loss or inactivation of tumor suppressor PTEN, or HER2 amplification all are significantly predictive of responsiveness to AZD5363. Additionally, correlation is also seen between the RAS mutation status of cell lines and resistance to it.

키나아제 분석
Caliper Off-Chip Incubation Mobility Shift assay
The ability of Capivasertib (AZD5363) and other compounds to inhibit the activity of AKT1, AKT2, and AKT3 is evaluated by the Caliper Off-Chip Incubation Mobility Shift assay. Active recombinant AKT1, AKT2, or AKT3 are incubated with a 5-FAM-labeled custom-synthesized peptide substrate together with increasing concentrations of this compound. Final reactions contained 1 to 3 nM AKT1, AKT2, or AKT3 enzymes; 1.5 mM peptide substrate; ATP at K m for each AKT isoform; 10 mM MgCl2, 4 mM DTT, 100 mM HEPES, and 0.015% Brij-35. The reactions are incubated at room temperature for 1 hour and stopped by the addition of buffer containing 100 mM HEPES, 0.015% Brij-35 solution, 0.1% coating reagent, 40 mM EDTA, and 5% DMSO. Plates are then analyzed using a Caliper LC3000, allowing for separation of peptide substrate and phosphorylated product by electrophoresis with subsequent detection and quantification of laser induced fluorescence.
생체 내(In vivo)

Oral dosing of Capivasertib (AZD5363) (100, 300 mg/kg) to nude mice causes dose- and time-dependent reduction of PRAS40, GSK3β, and S6 phosphorylation in BT474c xenografts, reversible increases in blood glucose concentrations, and dose-dependent decreases in 2[18F]fluoro-2-deoxy-d-glucose (18F-FDG) uptake in U87-MG xenografts. Chronic oral dosing of this compound (130, 200, and 300 mg/kg) causes dose-dependent growth inhibition of xenografts derived from various tumor types, including HER2+ breast cancer models.
참조

적용 분야 (Applications)

방법 바이오마커 이미지 PMID
Western blot pAKT / AKT / pGSK3β / GSK3β HER3 / pHER3 / HER2 / pHER2 / pPRAS40 / pS6 / p-4EBP1 / pFOXO / pERK / PARP / Cleaved PARP
S8019-WB1
26998062
Immunofluorescence p-Chk2 / γ-H2AX
S8019-IF1
29879757
Growth inhibition assay Cell viability
S8019-viability1
29879757

임상시험 정보 (Clinical Trial Information)

(데이터 출처 https://clinicaltrials.gov, 업데이트 날짜 2024-05-22)

NCT 번호 모집 조건 스폰서/협력자 시작일 단계
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