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AZD5363 (Capivasertib) Akt Inhibidor

Name: AZD5363 (Capivasertib)
Brand: Selleck Chemicals
SKU: S8019
Rating: 5 (154 reviews)

Cat. No.: S8019

Capivasertib (AZD5363) inhibe potentemente todas las isoformas de Akt (Akt1/Akt2/Akt3) con IC50 de 3 nM/8 nM/8 nM en ensayos sin células, similar a P70S6K/PKA y con menor actividad hacia ROCK1/2. Fase 2.

AZD5363 (Capivasertib) Akt Inhibidor Chemical Structure

Estructura química

Peso molecular: 428.92

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Control de calidad (Quality Control)

Lote: Pureza: 99.60%

99.60

Dianas relacionadas	PI3K mTOR GSK-3 ATM/ATR DNA-PK AMPK PDPK1 PTEN PP2A PDK
Otros Akt Inhibidores	SC79 MK-2206 Dihydrochloride Ipatasertib (GDC-0068) Perifosine GSK690693 Triciribine (API-2) Afuresertib (GSK2110183) CCT128930 A-674563 HCl AKTi-1/2 (AKT Inhibitor VIII)

Cultivo celular, tratamiento y concentración de trabajo
(Cell Culture, Treatment & Working Concentration)

Líneas celulares	Tipo de ensayo	Concentración	Tiempo de incubación	Descripción de la actividad	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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Información química, almacenamiento y estabilidad (Chemical Information, Storage & Stability)

Peso molecular	428.92	Fórmula	C₂₁H₂₅ClN₆O₂	Almacenamiento (Desde la fecha de recepción)	3 años-20°Cpolvo
Nº CAS	1143532-39-1	Descargar SDF		Almacenamiento de soluciones madre	1 año-80°Cen disolvente 1 mes-20°Cen disolvente
Sinónimos	N/A			Smiles	C1CN(CCC1(C(=O)NC(CCO)C2=CC=C(C=C2)Cl)N)C3=NC=NC4=C3C=CN4

Solubilidad (Solubility)

In vitro
Lote:

DMSO : 86 mg/mL (200.5 mM)
(El DMSO contaminado con humedad puede reducir la solubilidad. Usar DMSO fresco y anhidro.)

Ethanol : 20 mg/mL

Water : Insoluble

Calculadora de Molaridad

Masa	Concentración	Volumen	Peso molecular
=	×	×

Calculadora de Dilución Calculadora de Peso Molecular

In vivo Lote:
Homogeneous suspension	CMC-NA	≥5mg/ml	Taking the 1 mL working solution as an example, add 5 mg of this product to 1 ml of CMC-Na solution, mix evenly to obtain a homogeneous suspension with a final concentration of 5 mg/ml.
Homogeneous suspension	CMC-NA	≥5mg/ml	Taking the 1 mL working solution as an example, add 5 mg of this product to 1 ml of CMC-Na solution, mix evenly to obtain a homogeneous suspension with a final concentration of 5 mg/ml.
Homogeneous suspension	CMC-NA	≥5mg/ml	Taking the 1 mL working solution as an example, add 5 mg of this product to 1 ml of CMC-Na solution, mix evenly to obtain a homogeneous suspension with a final concentration of 5 mg/ml.
Clear solution	5%DMSO 1 40%PEG300 2 5%Tween80 3 50%ddH2O Validado por los laboratorios Selleck. Si necesita ajustes en esta formulación, contacte con nuestro equipo de ventas para pruebas personalizadas.	4.300mg/ml (10.03mM)	Taking the 1 mL working solution as an example, add 50 μL 86 mg/ml clarified DMSO stock solution to 400 μL PEG300, mix evenly to clarify it; add 50 μL Tween80 to the above system, mix evenly to clarify it; then continue to add 500 μL ddH2O to adjust the volume to 1 mL. The mixed solution should be used immediately for optimal results.
Homogeneous suspension	CMC-NA	≥5mg/ml	Taking the 1 mL working solution as an example, add 5 mg of this product to 1 ml of CMC-Na solution, mix evenly to obtain a homogeneous suspension with a final concentration of 5 mg/ml.
Homogeneous suspension	CMC-NA	≥5mg/ml	Taking the 1 mL working solution as an example, add 5 mg of this product to 1 ml of CMC-Na solution, mix evenly to obtain a homogeneous suspension with a final concentration of 5 mg/ml.

Calculadora de formulación in vivo (Solución clara)

Paso 1: Introduzca la información a continuación (Recomendado: Un animal adicional para tener en cuenta la pérdida durante el experimento)

Dosis: mg/kg Peso promedio de los animales: g Volumen de dosificación por animal:μL Número de animales:

Paso 2: Introduzca la formulación in vivo (Esto es solo la calculadora, no la formulación. Por favor, contáctenos primero si no hay una formulación in vivo en la sección de Solubilidad.)

% DMSO + % + % Tween 80 + % ddH₂O

%DMSO+ %

Resultados del cálculo:

Concentración de trabajo: mg/ml;

Método para preparar el líquido maestro de DMSO: mg fármaco predissuelto en μL DMSO ( Concentración del líquido maestro mg/mL, Por favor, contáctenos primero si la concentración excede la solubilidad del DMSO del lote del fármaco. )

Método para preparar la formulación in vivo: Tomar μL DMSO líquido maestro, luego añadirμL PEG300, mezclar y clarificar, luego añadirμL Tween 80, mezclar y clarificar, luego añadir μL ddH₂O, mezclar y clarificar.

Método para preparar la formulación in vivo: Tomar μL DMSO líquido maestro, luego añadir μL Aceite de maíz, mezclar y clarificar.

Nota: 1. Por favor, asegúrese de que el líquido esté claro antes de añadir el siguiente disolvente.
2. Asegúrese de añadir el (los) disolvente(s) en orden. Debe asegurarse de que la solución obtenida, en la adición anterior, sea una solución clara antes de proceder a añadir el siguiente disolvente. Se pueden utilizar métodos físicos como el vórtice, el ultrasonido o el baño de agua caliente para ayudar a la disolución.

Mecanismo de acción (Mechanism of Action)

Características	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
In vitro	Capivasertib (AZD5363) es un potente inhibidor de Akt con IC50 de 3 nM, 8 nM y 8 nM para Akt1, Akt2 y Akt3, respectivamente. Inhibe la fosforilación de los sustratos de Akt en las células con una potencia de aproximadamente 0,3 a 0,8 μM. Este compuesto inhibe la proliferación de 41 de 182 líneas celulares tumorales sólidas y hematológicas con una potencia de < 3 μM. Las mutaciones activadoras en PIK3CA, la pérdida o inactivación del supresor tumoral PTEN, o la amplificación de HER2 son significativamente predictivas de la respuesta a AZD5363. Además, también se observa una correlación entre el estado de mutación RAS de las líneas celulares y la resistencia al mismo.
Ensayo de quinasa	Ensayo de cambio de movilidad por incubación off-chip Caliper
Ensayo de quinasa	La capacidad de Capivasertib (AZD5363) y otros compuestos para inhibir la actividad de AKT1, AKT2 y AKT3 se evalúa mediante el ensayo Caliper Off-Chip Incubation Mobility Shift. Se incuban AKT1, AKT2 o AKT3 recombinantes activas con un sustrato peptídico sintetizado a medida marcado con 5-FAM junto con concentraciones crecientes de este compuesto. Las reacciones finales contenían de 1 a 3 nM de enzimas AKT1, AKT2 o AKT3; 1,5 mM de sustrato peptídico; ATP a K _m para cada isoforma de AKT; 10 mM de MgCl₂, 4 mM de DTT, 100 mM de HEPES y 0,015% de Brij-35. Las reacciones se incuban a temperatura ambiente durante 1 hora y se detienen mediante la adición de un tampón que contiene 100 mM de HEPES, 0,015% de solución de Brij-35, 0,1% de reactivo de recubrimiento, 40 mM de EDTA y 5% de DMSO. Las placas se analizan luego usando un Caliper LC3000, lo que permite la separación del sustrato peptídico y el producto fosforilado por electroforesis con posterior detección y cuantificación de la fluorescencia inducida por láser.
In vivo	La dosificación oral de Capivasertib (AZD5363) (100, 300 mg/kg) a ratones desnudos provoca una reducción dosis y tiempo-dependiente de la fosforilación de PRAS40, GSK3β y S6 en xenoinjertos BT474c, aumentos reversibles en las concentraciones de glucosa en sangre y disminuciones dosis-dependientes en la captación de 2[¹⁸F]fluoro-2-desoxi-d-glucosa (¹⁸F-FDG) en xenoinjertos U87-MG. La dosificación oral crónica de este compuesto (130, 200 y 300 mg/kg) provoca una inhibición del crecimiento dosis-dependiente de xenoinjertos derivados de varios tipos de tumores, incluidos modelos de cáncer de mama HER2+.
Referencias	[1] http://www.ncbi.nlm.nih.gov/pubmed/?term=23394218 [2] http://www.ncbi.nlm.nih.gov/pubmed/?term=22294718

Aplicaciones (Applications)

Métodos	Biomarcadores	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

Información del ensayo clínico (Clinical Trial Information)

(datos de https://clinicaltrials.gov, actualizado el 2024-05-22)

Número NCT	Reclutamiento	Condiciones	Patrocinador/Colaboradores	Fecha de inicio	Fases
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

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