Home Protein Tyrosine Kinase c-Kit inhibitor Amuvatinib (MP-470)

solo para uso en investigación

Amuvatinib (MP-470) c-Kit inhibitor

Cat. No.: S1244

Amuvatinib (MP-470, HPK 56) is a potent and multi-targeted inhibitor of c-Kit, PDGFRα and Flt3 with IC50 of 10 nM, 40 nM and 81 nM, respectively. It suppresses c-MET and c-RET, and is also active as a DNA repair protein Rad51 inhibitor with antineoplastic activity. Phase 2.
Amuvatinib (MP-470) c-Kit inhibitor Chemical Structure

Estructura química

Peso molecular: 447.51

Saltar a

Control de calidad (Quality Control)

Lote: Pureza: 99.75%
99.75

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

Líneas celulares Tipo de ensayo Concentración Tiempo de incubación Formulación Descripción de la actividad PMID
GIST Function assay Inhibition of AXL in human GIST cells, IC50<1μM 26555154
DAOY qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for DAOY cells 29435139
A673 qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for A673 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
NB1643 qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for NB1643 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
OHS-50 qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for OHS-50 cells 29435139
Caco-2 Function assay 48 hrs Determination of IC50 values for inhibition of SARS-CoV-2 induced cytotoxicity of Caco-2 cells after 48 hours by high content imaging, IC50=0.02μM ChEMBL
Caco-2 Function assay 48 hrs Toxicity against Caco-2 cells determined at 48 hours by intracellular ATP concentration using the CellTiter-Glo Luminescent Cell Viability Assay, CC50=0.06μM ChEMBL
GIST882 Function assay 4 days Inhibition of c-kit gain of function mutant in human GIST882 cells measured after 4 days by sulforhodamine B assay, IC50=1.6μM ChEMBL
GIST882 Function assay 96 hrs Inhibition of c-kit gain of function mutant in human GIST882 cells after 96 hrs by Cell-Titer Glo luciferase assay, IC50=1.6μM ChEMBL
MIAPaCa2 Function assay 4 days Inhibition of PDGFRA in human MIAPaCa2 cells measured after 4 days by sulforhodamine B assay, IC50=2.1μM ChEMBL
PANC1 Function assay 4 days Inhibition of PDGFRA in human PANC1 cells measured after 4 days by sulforhodamine B assay, IC50=3μM ChEMBL
SF-767 Cytotoxicity assay 1 uM 24 hrs Cytotoxicity against human SF-767 cells assessed as cell death at 1 uM after 24 hrs by MTS assay ChEMBL
SF-767 Cytotoxicity assay 1 uM 24 hrs Cytotoxicity against human SF-767 cells assessed as cell death at 1 uM in presence of 800Gy ionizing radiation after 24 hrs by MTS assay ChEMBL
SBcl2 Antitumor assay 5 days Antitumor activity against human SBcl2 cells xenografted in ip dosed athymic nude mouse assessed as reduction in tumor growth administered as qd for 5 days ChEMBL
HT-29 Function assay Suppression of ionizing radiation-induced Rad51 expression in human HT-29 cells pretreated with compound followed by ionizing radiation by Western blot analysis ChEMBL
Haga clic para ver más datos experimentales de líneas celulares

Información química, almacenamiento y estabilidad (Chemical Information, Storage & Stability)

Peso molecular 447.51 Fórmula

C23H21N5O3S

 Almacenamiento (Desde la fecha de recepción)
Nº CAS 850879-09-3 Descargar SDF Almacenamiento de soluciones madre

Sinónimos HPK 56 Smiles C1CN(CCN1C2=NC=NC3=C2OC4=CC=CC=C43)C(=S)NCC5=CC6=C(C=C5)OCO6

Solubilidad (Solubility)

In vitro
Lote:

DMSO : 32 mg/mL (71.5 mM)
(El DMSO contaminado con humedad puede reducir la solubilidad. Usar DMSO fresco y anhidro.)

Water : Insoluble

Ethanol : Insoluble

Calculadora de Molaridad

Masa Concentración Volumen Peso molecular
Calculadora de Dilución Calculadora de Peso Molecular

In vivo
Lote:

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)

mg/kg g μL

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)

Targets/IC50/Ki
c-Met
RAD51
c-RET
c-Kit (D816H)
10 nM
PDGFRα (V561D)
40 nM
FLT3 (D835Y)
81 nM
In vitro

The hydrochloride salt of Amuvatinib (MP-470) inhibits several mutants of c-Kit, including c-KitD816V, c-KitD816H, c-KitV560G, and c-KitV654A, as well as a Flt3 mutant (Flt3D835Y) and two PDGFRα mutants (PDGFRαV561D and PDGFRαD842V), with IC50 of 10 nM to 8.4 μM. It also binds to and inhibits several c-Kit mutants, including c-KitK642E, c-KitD816V, and c-KitK642E/D816V. This compound potently inhibits the proliferation of OVCAR-3, A549, NCI-H647, DMS-153, and DMS-114 cells, with IC50 of 0.9 μM–7.86 μM. It also inhibits c-Kit and PDGFRα, with IC50 values of 31 μM and 27 μM, respectively. It demonstrates potent cytotoxicity against MiaPaCa-2, PANC-1, and GIST882 cells, with IC50 of 1.6 μM to 3.0 μM. In MDA-MB-231 cells, it (1 μM) inhibits tyrosine phosphorylation of AXL. In LNCaP and PC-3, but not DU145 cells, it exhibits cytotoxicity with IC50 of 4 μM and 8 μM, respectively, and induces apoptosis at 10 μM. In LNCaP cells, it (10 μM) elicits G1 arrest and decreases phosphorylation of Akt and ERK1/2. In SF767 cells, it (10 μM) inhibits c-Met phosphorylation and sensitizes cells to radiation. In combination with radiation, it (10 μM) inhibits glycogen synthase kinase (GSK)3β activity, induces apoptosis, and disrupts the repair of dsDNA breaks probably through suppression of Rad51.

Ensayo de quinasa
Ensayo de inhibición de quinasa de c-Kit y PDGFRα
Para la prueba de actividad inhibidora contra c-Kit y PDGFRα, las enzimas se incuban con concentraciones variables de Amuvatinib (MP-470) y γ-32P-ATP radiomarcado. Después de 30 minutos, las mezclas de reacción se someten a electroforesis en un gel de acrilamida y se ensaya la autofosforilación, cuantificada por la cantidad de radiactividad incorporada en la enzima.
In vivo

In mice xenograft models of HT-29, A549, and SB-CL2 cells, Amuvatinib (MP-470) (10 mg/kg–75 mg/kg via i.p. or 50 mg/kg–200 mg/kg via p.o.) inhibits tumor growth. In mice bearing LNCaP xenograft, this compound (20 mg/kg) combined with Erlotinib significantly induces tumor growth inhibition (TGI).

Referencias
  • [4] https://pubmed.ncbi.nlm.nih.gov/19432987/
  • [5] https://pubmed.ncbi.nlm.nih.gov/20028557/
  • [6] https://pubmed.ncbi.nlm.nih.gov/21903282/
  • [7] https://pubmed.ncbi.nlm.nih.gov/20563581/

Aplicaciones (Applications)

Métodos Biomarcadores Imágenes PMID
Growth inhibition assay Cell viability
S1244-viability1
24950457
Western blot p-AXL / AXL / p-AKT / AKT / ERK / Rad51
S1244-WB1
24950457

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
NCT01357395 Completed
Small Cell Lung Carcinoma
Astex Pharmaceuticals Inc.
 May 2011 Phase 2