Entrectinib (Rxdx-101) Trk receptor inhibiteur

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Contrôle Qualité

Lot : Pureté : 99.93%

99.93

Cibles apparentées	EGFR VEGFR PDGFR FGFR c-Met Src MEK CSF-1R FLT3 HER2
Autre Trk receptor Inhibiteurs	ANA-12 GW441756 7,8-Dihydroxyflavone GNF-5837 Selitrectinib (LOXO-195) Altiratinib LM22B-10 N-Acetyl-5-hydroxytryptamine PF-06273340 CH7057288

Culture cellulaire, traitement et concentration de travail

Lignées cellulaires	Type dessai	Concentration	Temps dincubation	Description de lactivité	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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Informations chimiques, stockage et stabilité

Poids moléculaire	560.64	Formule	C₃₁H₃₄F₂N₆O₂	Stockage (À compter de la date de réception)	3 ans-20°Cpoudre
N° CAS	1108743-60-7	Télécharger le SDF		Stockage des solutions mères	1 an-80°Cen solvant 1 mois-20°Cen solvant
Synonymes	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

Solubilité

In vitro
Lot:

DMSO : 100 mg/mL (178.36 mM)
(Le DMSO contaminé par lhumidité peut réduire la solubilité. Utiliser du DMSO frais et anhydre.)

Ethanol : 100 mg/mL

Water : Insoluble

Calculateur de molarité

Masse	Concentration	Volume	Poids moléculaire
=	×	×

Calculateur de dilution Calculateur de poids moléculaire

In vivo Lot:
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 Validé par les laboratoires Selleck. Si vous avez besoin dajustements à cette formulation, contactez notre équipe commerciale pour des tests personnalisés.	5.000mg/ml (8.92mM)	Taking the 1 mL working solution as an example, add 50 μL of 100 mg/ml clarified DMSO stock solution to 400 μL of PEG300, mix evenly to clarify it; add 50 μL of Tween80 to the above system, mix evenly to make it clear; then continue to add 500 μL of 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.
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.

Calculateur de formulation in vivo (Solution claire)

Étape 1 : Saisir les informations ci-dessous (Recommandé : Un animal supplémentaire pour tenir compte des pertes pendant lexpérience)

Dosage : mg/kg Poids moyen des animaux : g Volume de dosage par animal :μL Nombre danimaux :

Étape 2 : Saisir la formulation in vivo (Ceci est seulement le calculateur, pas la formulation. Veuillez nous contacter dabord sil ny a pas de formulation in vivo dans la section Solubilité.)

% DMSO + % + % Tween 80 + % ddH₂O

%DMSO+ %

Résultats du calcul :

Concentration de travail : mg/ml;

Méthode de préparation du liquide maître DMSO : mg médicament prédissous dans μL DMSO ( Concentration du liquide maître mg/mL, Veuillez nous contacter dabord si la concentration dépasse la solubilité du DMSO du lot de médicament. )

Méthode de préparation de la formulation in vivo : Prendre μL DMSO liquide maître, puis ajouterμL PEG300, mélanger et clarifier, puis ajouterμL Tween 80, mélanger et clarifier, puis ajouter μL ddH₂O, mélanger et clarifier.

Méthode de préparation de la formulation in vivo : Prendre μL DMSO liquide maître, puis ajouter μL Huile de maïs, mélanger et clarifier.

Note : 1. Veuillez vous assurer que le liquide est clair avant dajouter le solvant suivant.
2. Assurez-vous dajouter le(s) solvant(s) dans lordre. Vous devez vous assurer que la solution obtenue, lors de lajout précédent, est une solution claire avant de procéder à lajout du solvant suivant. Des méthodes physiques telles que le vortex, les ultrasons ou le bain-marie chaud peuvent être utilisées pour faciliter la dissolution.

Mécanisme daction

Targets/IC₅₀/Ki	TrkA TrkB TrkC ROS1 ALK
In vitro	Entrectinib bloque sélectivement la prolifération des lignées cellulaires dépendantes d'ALK et inhibe puissamment la signalisation dépendante d'ALK. Ce composé inhibe également fortement la croissance cellulaire de la lignée cellulaire de NSCLC NCI-H2228 portant le réarrangement EML4-ALK.
In vivo	Chez les souris porteuses de xénogreffes Karpas-299 et SR-786, Entrectinib (p.o.) induit une régression tumorale complète. Chez les souris transgéniques NPM-ALK, ce composé induit une régression complète des masses tumorales observées dans le thymus et les ganglions lymphatiques. Dans le modèle de xénogreffe NB, le cotraitement avec ce composé a amélioré l'efficacité de la chimiothérapie conventionnelle.
Références	[1] https://pubmed.ncbi.nlm.nih.gov/26457764/ [2] http://mct.aacrjournals.org/content/8/12_Supplement/A244.short [3] http://cancerres.aacrjournals.org/content/75/15_Supplement/5390 [4] https://pubmed.ncbi.nlm.nih.gov/36101520/ [5] https://pubmed.ncbi.nlm.nih.gov/33229458/

Applications

Méthodes	Biomarqueurs	Images	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		26735175
Growth inhibition assay	Cell viability		26172300

Informations sur lessai clinique

(données du https://clinicaltrials.gov, mis à jour le 2024-05-22)

Numéro NCT	Recrutement	Conditions	Promoteur/Collaborateurs	Date de début	Phases
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

Support technique

Instructions de manipulation

Tel: +1-832-582-8158 Ext:3

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C1=C0/X	C1:	LOG(C1):
C2=C1/X	C2:	LOG(C2):
C3=C2/X	C3:	LOG(C3):
C4=C3/X	C4:	LOG(C4):
C5=C4/X	C5:	LOG(C5):
C6=C5/X	C6:	LOG(C6):
C7=C6/X	C7:	LOG(C7):
C8=C7/X	C8:	LOG(C8):

Structure chimique

Poids moléculaire: 560.64