Home Protein Tyrosine Kinase Trk receptor inhibitor Entrectinib (Rxdx-101)

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Entrectinib (Rxdx-101) Trk receptor inhibitor

Cat. No.: S7998

Entrectinib is an orally bioavailable pan-TrkA/B/C, ROS1 and ALK inhibitor with IC50 ranging between 0.1 and 1.7 nM. Entrectinib (RXDX-101) induces autophagy. Phase 2.
Entrectinib (Rxdx-101) Trk receptor inhibitor Chemical Structure

Estructura química

Peso molecular: 560.64

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Control de calidad (Quality Control)

Lote: Pureza: 99.93%
99.93

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
BAF3 Function assay 72 hrs Inhibition of human TEL (336 residues) fused-TRKB (455 to 822 residues) (unknown origin) expressed in mouse BAF3 cells assessed as cell growth inhibition after 72 hrs by cell titer-glo assay, IC50 = 0.003 μM. 27003761
BAF3 Function assay 72 hrs Inhibition of human TEL (336 residues) fused-TRKA (440 to 796 residues) (unknown origin) expressed in mouse BAF3 cells assessed as cell growth inhibition after 72 hrs by cell titer-glo assay, IC50 = 0.003 μM. 27003761
BAF3 Function assay 72 hrs Inhibition of human TEL (336 residues) fused-TRKC (454 to 825 residues) (unknown origin) expressed in mouse BAF3 cells assessed as cell growth inhibition after 72 hrs by cell titer-glo assay, IC50 = 0.003 μM. 27003761
BAF3 Function assay 72 hrs Inhibition of human TEL (336 residues) fused-ROS1 (1891 to 2347 residues) (unknown origin) expressed in mouse BAF3 cells assessed as cell growth inhibition after 72 hrs by cell titer-glo assay, IC50 = 0.005 μM. 27003761
KM12 Antiproliferative assay 72 hrs Antiproliferative activity against human KM12 cells expressing TRKA protein incubated for 72 hrs by cell titer-glo assay, IC50 = 0.017 μM. 27003761
SU-DHL1 Antiproliferative assay 72 hrs Antiproliferative activity against human SU-DHL1 cells expressing ALK protein incubated for 72 hrs by cell titer-glo assay, IC50 = 0.024 μM. 27003761
BAF3 Function assay 72 hrs Inhibition of wild type EML4-ALK (unknown origin) expressed in mouse BAF3 cells assessed as cell growth inhibition after 72 hrs by cell titer-glo assay, IC50 = 0.028 μM. 27003761
KARPAS299 Antiproliferative assay 72 hrs Antiproliferative activity against human KARPAS299 cells incubated for 72 hrs by cell titer-glo assay, IC50 = 0.031 μM. 27003761
SUP-M2 Antiproliferative assay 72 hrs Antiproliferative activity against human SUP-M2 cells expressing ALK protein incubated for 72 hrs by cell titer-glo assay, IC50 = 0.041 μM. 27003761
BAF3 Function assay 72 hrs Inhibition of EML4-ALK L1196M mutant (unknown origin) expressed in mouse BAF3 cells assessed as cell growth inhibition after 72 hrs by cell titer-glo assay, IC50 = 0.067 μM. 27003761
NCI-H2228 Antiproliferative assay 72 hrs Antiproliferative activity against human NCI-H2228 cells expressing ALK protein incubated for 72 hrs by cell titer-glo assay, IC50 = 0.068 μM. 27003761
MV411 Antiproliferative assay 72 hrs Antiproliferative activity against human MV411 cells incubated for 72 hrs by cell titer-glo assay, IC50 = 0.081 μM. 27003761
SR786 Antiproliferative assay 72 hrs Antiproliferative activity against human SR786 cells expressing ALK protein incubated for 72 hrs by cell titer-glo assay, IC50 = 0.081 μM. 27003761
BAF3 Function assay 72 hrs Inhibition of EML4-ALK G1202R mutant (unknown origin) expressed in mouse BAF3 cells assessed as cell growth inhibition after 72 hrs by cell titer-glo assay, IC50 = 0.897 μM. 27003761
BA/F3 Cytotoxicity assay 72 hrs Cytotoxicity against mouse IL-3 dependent BA/F3 cells incubated for 72 hrs by cell titer-glo assay, IC50 = 2.104 μM. 27003761
KM12 Function assay 2 hrs Inhibition of TPM3-TRKA phosphorylation in human KM12 cells at low concentration after 2 hrs by Western blot analysis 27003761
KM12 Function assay 2 hrs Inhibition of TPM3-TRKA phosphorylation in human KM12 cells assessed as suppression of MAPK phosphorylation at low concentration after 2 hrs by Western blot analysis 27003761
KM12 Function assay 2 hrs Inhibition of TPM3-TRKA phosphorylation in human KM12 cells assessed as suppression of PLCgamma1 phosphorylation at low concentration after 2 hrs by Western blot analysis 27003761
KM12 Function assay 2 hrs Inhibition of TPM3-TRKA phosphorylation in human KM12 cells assessed as suppression of AKT phosphorylation at low concentration after 2 hrs by Western blot analysis 27003761
KM12 Function assay 2 hrs Inhibition of TPM3-TRKA phosphorylation in human KM12 cells assessed as suppression of S6 phosphorylation at low concentration after 2 hrs by Western blot analysis 27003761
KARPAS299 Function assay 60 mg/kg 12 hrs Ex vivo inhibition of NPM-ALK phosphorylation in SCID mouse xenografted with human KARPAS299 cells at 60 mg/kg, po administered as single dose measured after 12 hrs by Western blot analysis 27003761
KARPAS299 Function assay 60 mg/kg 18 hrs Ex vivo inhibition of NPM-ALK phosphorylation in SCID mouse xenografted with human KARPAS299 cells at 60 mg/kg, po administered as single dose measured after 18 hrs by Western blot analysis 27003761
KARPAS299 Function assay 60 mg/kg 12 hrs Ex vivo inhibition of NPM-ALK phosphorylation in SCID mouse xenografted with human KARPAS299 cells assessed as suppression of STAT3 phosphorylation at 60 mg/kg, po administered as single dose measured after 12 hrs by Western blot analysis 27003761
KARPAS299 Function assay 60 mg/kg 18 hrs In vivo inhibition of NPM-ALK phosphorylation in SCID mouse xenografted with human KARPAS299 cells assessed as suppression of STAT3 phosphorylation at 60 mg/kg, po administered as single dose measured after 18 hrs by Western blot analysis 27003761
NCI-H2228 Antitumor assay 30 to 60 mg/kg 10 days Antitumor activity against human NCI-H2228 cells xenografted in athymic nu/nu mouse assessed as tumor growth inhibition at 30 to 60 mg/kg, po bid administered for 10 days 27003761
NCI-H2228 Function assay 60 mg/kg 12 hrs Ex vivo inhibition of EML4-ALK phosphorylation in athymic nu/nu mouse xenografted with human NCI-H2228 cells at 60 mg/kg, po administered as single dose measured after 12 hrs by Western blot analysis 27003761
NCI-H2228 Function assay 60 mg/kg 18 hrs Ex vivo inhibition of EML4-ALK phosphorylation in athymic nu/nu mouse xenografted with human NCI-H2228 cells at 60 mg/kg, po administered as single dose measured after 18 hrs by Western blot analysis 27003761
NCI-H2228 Function assay 60 mg/kg 12 hrs Ex vivo inhibition of EML4-ALK phosphorylation in athymic nu/nu mouse xenografted with human NCI-H2228 cells assessed as suppression of AKT phosphorylation at 60 mg/kg, po administered as single dose measured after 12 hrs by Western blot analysis 27003761
NCI-H2228 Function assay 60 mg/kg 18 hrs Ex vivo inhibition of EML4-ALK phosphorylation in athymic nu/nu mouse xenografted with human NCI-H2228 cells assessed as suppression of AKT phosphorylation at 60 mg/kg, po administered as single dose measured after 18 hrs by Western blot analysis 27003761
KARPAS299 Antitumor assay 30 to 60 mg/kg 10 days Antitumor activity against human KARPAS299 cells xenografted in SCID mouse assessed as tumor growth inhibition at 30 to 60 mg/kg, po bid administered for 10 days 27003761
KARPAS299 Antitumor assay 30 to 60 mg/kg 10 days Antitumor activity against human KARPAS299 cells xenografted in SCID mouse assessed as tumor free cured mouse at 30 to 60 mg/kg, po bid administered for 10 days measured on day 90 27003761
KARPAS299 Function assay 2 hrs Inhibition of NPM/ALK autophosphorylation in human KARPAS299 cells at very low concentration after 2 hrs by Western blot analysis 27003761
NCI-H2228 Function assay 2 hrs Inhibition of NPM/ALK autophosphorylation in human NCI-H2228 cells at very low concentration after 2 hrs by Western blot analysis 27003761
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Información química, almacenamiento y estabilidad (Chemical Information, Storage & Stability)

Peso molecular 560.64 Fórmula

C31H34F2N6O2

 Almacenamiento (Desde la fecha de recepción)
Nº CAS 1108743-60-7 Descargar SDF Almacenamiento de soluciones madre

Sinónimos RXDX-101, NMS-E628 Smiles CN1CCN(CC1)C2=CC(=C(C=C2)C(=O)NC3=NNC4=C3C=C(C=C4)CC5=CC(=CC(=C5)F)F)NC6CCOCC6

Solubilidad (Solubility)

In vitro
Lote:

DMSO : 100 mg/mL (178.36 mM)
(El DMSO contaminado con humedad puede reducir la solubilidad. Usar DMSO fresco y anhidro.)

Ethanol : 100 mg/mL

Water : 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
TrkA
TrkB
TrkC
ROS1
ALK
In vitro

Entrectinib selectively blocks proliferation of ALK-dependent cell lines and potently inhibits ALK‐dependent signaling. This compound also highly inhibits cell growth of the NSCLC cell line NCI‐H2228 bearing the EML4-ALK rearrangement.

In vivo

In mice bearing Karpas-299 and SR-786 xenografts, Entrectinib (p.o.) induces complete tumor regression. In NPM-ALK transgenic mice, this compound induces complete regression of tumor masses observed in the thymus and in lymph nodes.

In the NB xenograft model, this compound cotreatment enhanced the efficacy of conventional chemotherapy.

Referencias
  • [4] https://pubmed.ncbi.nlm.nih.gov/36101520/
  • [5] https://pubmed.ncbi.nlm.nih.gov/33229458/

Aplicaciones (Applications)

Métodos Biomarcadores Imágenes PMID
Western blot Cyclin A1 / Cyclin E1 / p27 / p21 p-ALK / ALK / p-ERK / ERK / p-STAT3 / STAT3 pTrkA-Y490 / TrkA / p-PLCγ-Y783 / PLCγ pAKT / AKT
S7998-WB1
26735175
Growth inhibition assay Cell viability
S7998-viability1
26172300

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
NCT05770544 Recruiting
Solid Tumor|Haematological Malignancy|Malignancy|Malignant Neoplasm|Lymphoproliferative Disorders|Neoplasms by Histologic Type|Neoplasms by Site|Cancer|Brain Neoplasms|Melanoma|Glioma
Cancer Research UK|University of Manchester|University of Birmingham|Royal Marsden NHS Foundation Trust|Hoffmann-La Roche
 June 2024 Phase 2|Phase 3
NCT04551495 Recruiting
Invasive Lobular Breast Carcinoma|ER+ Breast Cancer|HER2-negative Breast Cancer
Jules Bordet Institute|Hoffmann-La Roche
 January 14 2021 Phase 2
NCT04226833 Completed
Hepatic Insufficiency
Hoffmann-La Roche
 February 11 2020 Phase 1
NCT03796013 Completed
Healthy Volunteers
Genentech Inc.
 January 10 2019 Phase 1