Entrectinib (Rxdx-101) Trk receptor remmer

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Batch: Zuiverheid: 99.93%

99.93

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

Celkweek, behandeling & werkconcentratie

Cellijnen	Assaytype	Concentratie	Incubatietijd	Activiteitsbeschrijving	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
Klik om meer experimentele gegevens over de cellijn te bekijken

Chemische informatie, Opslag en Stabiliteit

Moleculair gewicht	560.64	Formule	C₃₁H₃₄F₂N₆O₂	Opslag (Vanaf de ontvangstdatum)	3 jaar-20°Cpoeder
CAS-nr.	1108743-60-7	SDF downloaden		Opslag van stamoplossingen	1 jaar-80°Cin oplosmiddel 1 maand-20°Cin oplosmiddel
Synoniemen	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

Oplosbaarheid

In vitro
Batch:

DMSO : 100 mg/mL (178.36 mM)
(Met vocht verontreinigde DMSO kan de oplosbaarheid verminderen. Gebruik verse, watervrije DMSO.)

Ethanol : 100 mg/mL

Water : Insoluble

Molariteitscalculator

Massa	Concentratie	Volume	Moleculair gewicht
=	×	×

Verdunningscalculator Moleculair gewicht calculator

In vivo Batch:
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 Gevalideerd door Selleck labs. Mocht u aanpassingen aan deze formulering nodig hebben, neem dan contact op met ons verkoopteam voor aangepaste tests.	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.

In vivo Formuleringscalculator (Heldere oplossing)

Stap 1: Voer de onderstaande informatie in (Aanbevolen: Een extra dier voor het geval van verlies tijdens het experiment)

Dosering: mg/kg Gemiddeld gewicht van dieren: g Doseervolume per dier:μL Aantal dieren:

Stap 2: Voer de in vivo formulering in (Dit is alleen de calculator, geen formulering. Neem eerst contact met ons op als er geen in vivo formulering is in het gedeelte Oplosbaarheid.)

% DMSO + % + % Tween 80 + % ddH₂O

%DMSO+ %

Berekeningsresultaten:

Werkconcentratie: mg/ml;

Methode voor het bereiden van DMSO-mastervloeistof: mg geneesmiddel vooraf opgelost in μL DMSO ( Concentratie mastervloeistof mg/mL, Neem eerst contact met ons op als de concentratie de DMSO-oplosbaarheid van de partij geneesmiddel overschrijdt. )

Methode voor het bereiden van in vivo formulering: Neem μL DMSO mastervloeistof, voeg vervolgens toeμL PEG300, mengen en helder maken, voeg vervolgens toeμL Tween 80, mengen en helder maken, voeg vervolgens toe μL ddH₂O, mengen en helder maken.

Methode voor het bereiden van in vivo formulering: Neem μL DMSO mastervloeistof, voeg vervolgens toe μL Maïsolie, mengen en helder maken.

Opmerking: 1. Zorg ervoor dat de vloeistof helder is voordat u het volgende oplosmiddel toevoegt.
2. Zorg ervoor dat u het/de oplosmiddel(en) in de juiste volgorde toevoegt. U moet ervoor zorgen dat de verkregen oplossing, bij de vorige toevoeging, een heldere oplossing is voordat u verdergaat met het toevoegen van het volgende oplosmiddel. Fysische methoden zoals vortexen, echografie of een warmwaterbad kunnen worden gebruikt om het oplossen te bevorderen.

Werkingsmechanisme

Targets/IC₅₀/Ki	TrkA TrkB TrkC ROS1 ALK
In vitro	Entrectinib blokkeert selectief de proliferatie van ALK-afhankelijke cellijnen en remt krachtig ALK-afhankelijke signalering. Deze verbinding remt ook sterk de celgroei van de NSCLC-cellijn NCI-H2228 die de EML4-ALK-rearrangement draagt.
In vivo	Bij muizen met Karpas-299 en SR-786 xenografts induceert Entrectinib (p.o.) volledige tumorregressie. Bij NPM-ALK transgene muizen induceert deze verbinding volledige regressie van tumormassa's waargenomen in de thymus en in de lymfeklieren. In het NB-xenograftmodel verbeterde deze verbinding de werkzaamheid van conventionele chemotherapie bij co-behandeling.
Referenties	[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/

Toepassingen

Methoden	Biomarkers	Afbeeldingen	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

Informatie klinische proef

(gegevens van https://clinicaltrials.gov, bijgewerkt op 2024-05-22)

NCT-nummer	Rekrutering	Aandoeningen	Sponsor/Medewerkers	Startdatum	Fasen
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

Technische ondersteuning

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C5=C4/X	C5:	LOG(C5):
C6=C5/X	C6:	LOG(C6):
C7=C6/X	C7:	LOG(C7):
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Chemische structuur

Moleculair gewicht: 560.64