Lorlatinib (PF-6463922) ALK inhibiteur

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Contrôle qualité

Lot : Pureté : 99.95%

99.95

Cibles apparentées	EGFR VEGFR PDGFR FGFR c-Met Src MEK CSF-1R FLT3 HER2
Autre ALK Inhibiteurs	TAE684 (NVP-TAE684) GSK1838705A Repotrectinib (TPX-0005) AZD3463 Ensartinib dihydrochloride AP26113-analog (ALK-IN-1) ASP3026 NVL-655 (Neladalkib) Envonalkib Belizatinib (TSR-011)

Culture cellulaire, traitement et concentration de travail

Lignées cellulaires	Type dessai	Temps dincubation	Description de lactivité	PMID
NIH-3T3	Function assay	1 hr	Inhibition of human EML4-fused ALK F1174L mutant expressed in mouse NIH-3T3 cells assessed as phospho-ALK level after 1 hr by sandwich ELISA, IC50 = 0.0002 μM.	24819116
NIH/3T3	Function assay		Inhibition of wild type EML4/ALK F1174L mutant (unknown origin) expressed in NIH/3T3 cells, IC50 = 0.0002 μM.	28431340
BAF3	Antiproliferative assay	72 hrs	Antiproliferative activity against mouse BAF3 cells harboring CD74-ROS1 after 72 hrs by SRB or CCK8 assay, IC50 = 0.0012 μM.	29288940
NIH-3T3	Function assay	1 hr	Inhibition of wild type human EML4-fused ALK expressed in mouse NIH-3T3 cells assessed as phosphorylated ALK level after 1 hr by sandwich ELISA, IC50 = 0.0013 μM.	24819116
NIH/3T3	Function assay		Inhibition of wild type EML4/ALK (unknown origin) expressed in NIH/3T3 cells, IC50 = 0.0013 μM.	28431340
NIH-3T3	Function assay	1 hr	Inhibition of human EML4-fused ALK C1156Y mutant expressed in mouse NIH-3T3 cells assessed as phospho-ALK level after 1 hr by sandwich ELISA, IC50 = 0.0016 μM.	24819116
NIH/3T3	Function assay		Inhibition of wild type EML4/ALK C1156Y mutant (unknown origin) expressed in NIH/3T3 cells, IC50 = 0.0016 μM.	28431340
BAF3	Antiproliferative assay	72 hrs	Antiproliferative activity against mouse BAF3 cells harboring EML4-ALK after 72 hrs by SRB or CCK8 assay, IC50 = 0.0029 μM.	29288940
KARPAS299	Antiproliferative assay	72 hrs	Antiproliferative activity against human KARPAS299 cells harboring NPM-ALK after 72 hrs by SRB or CCK8 assay, IC50 = 0.003 μM.	29288940
NIH-3T3	Function assay	1 hr	Inhibition of human EML4-fused ALK S1206Y mutant expressed in mouse NIH-3T3 cells assessed as phospho-ALK level after 1 hr by sandwich ELISA, IC50 = 0.0042 μM.	24819116
NIH/3T3	Function assay		Inhibition of wild type EML4/ALK S1206Y mutant (unknown origin) expressed in NIH/3T3 cells, IC50 = 0.0042 μM.	28431340
SU-DHL1	Antiproliferative assay	72 hrs	Antiproliferative activity against human SU-DHL1 cells harboring NPM-ALK after 72 hrs by SRB or CCK8 assay, IC50 = 0.0049 μM.	29288940
NCI-H3122	Antiproliferative assay	72 hrs	Antiproliferative activity against human NCI-H3122 cells after 72 hrs by SRB or CCK8 assay, IC50 = 0.0078 μM.	29288940
NIH-3T3	Function assay	1 hr	Inhibition of human EML4-fused ALK L1152R mutant expressed in mouse NIH-3T3 cells assessed as phospho-ALK level after 1 hr by sandwich ELISA, IC50 = 0.009 μM.	24819116
NIH/3T3	Function assay		Inhibition of wild type EML4/ALK L1152R mutant (unknown origin) expressed in NIH/3T3 cells, IC50 = 0.009 μM.	28431340
NIH-3T3	Function assay	1 hr	Inhibition of human EML4-fused ALK G1269A mutant expressed in mouse NIH-3T3 cells assessed as phospho-ALK level after 1 hr by sandwich ELISA, IC50 = 0.015 μM.	24819116
NIH/3T3	Function assay		Inhibition of wild type EML4/ALK G1269A mutant (unknown origin) expressed in NIH/3T3 cells, IC50 = 0.015 μM.	28431340
NIH-3T3	Function assay	1 hr	Inhibition of human EML4-fused ALK L1196M mutant expressed in mouse NIH-3T3 cells assessed as phospho-ALK level after 1 hr by sandwich ELISA, IC50 = 0.021 μM.	24819116
NIH/3T3	Function assay		Inhibition of wild type EML4/ALK L1196M mutant (unknown origin) expressed in NIH/3T3 cells, IC50 = 0.021 μM.	28431340
NIH-3T3	Function assay	1 hr	Inhibition of human EML4-fused ALK 1151Tins mutant expressed in mouse NIH-3T3 cells assessed as phospho-ALK level after 1 hr by sandwich ELISA, IC50 = 0.038 μM.	24819116
NIH/3T3	Function assay		Inhibition of wild type EML4/ALK 1151Tins mutant (unknown origin) expressed in NIH/3T3 cells, IC50 = 0.038 μM.	28431340
BAF3	Antiproliferative assay	72 hrs	Antiproliferative activity against mouse BAF3 cells harboring EML4-ALK L1196M mutant after 72 hrs by SRB or CCK8 assay, IC50 = 0.0424 μM.	29288940
NIH-3T3	Function assay	1 hr	Inhibition of human EML4-fused ALK G1202R mutant expressed in mouse NIH-3T3 cells assessed as phospho-ALK level after 1 hr by sandwich ELISA, IC50 = 0.077 μM.	24819116
NIH/3T3	Function assay		Inhibition of wild type EML4/ALK G1202R mutant (unknown origin) expressed in NIH/3T3 cells, IC50 = 0.077 μM.	28431340
BAF3	Antiproliferative assay	72 hrs	Antiproliferative activity against mouse BAF3 cells harboring EML4-ALK G1202R mutant after 72 hrs by SRB or CCK8 assay, IC50 = 0.2 μM.	29288940
BAF3	Antiproliferative assay	72 hrs	Antiproliferative activity against mouse BAF3 cells harboring CD74-ROS1 G2032R mutant after 72 hrs by SRB or CCK8 assay, IC50 = 0.262 μM.	29288940
HCC78	Antiproliferative assay	72 hrs	Antiproliferative activity against human HCC78 cells harboring SLC34A2-ROS1 after 72 hrs by SRB or CCK8 assay, IC50 = 0.357 μM.	29288940
SU-DHL1	Function assay		Inhibition of ALK in human SU-DHL1 cells assessed as reduction in STAT3 phosphorylation at Y705 residue at 20 to 80 nM after 1 hr by Western blot analysis	29288940
SU-DHL1	Function assay		Inhibition of ALK in human SU-DHL1 cells assessed as reduction in Akt phosphorylation at S473 residue at 20 to 80 nM after 1 hr by Western blot analysis	29288940
SU-DHL1	Function assay		Inhibition of ALK phosphorylation at Y1278 residue in human SU-DHL1 cells at 20 to 80 nM after 1 hr by Western blot analysis	29288940
SU-DHL1	Function assay		Inhibition of ALK in human SU-DHL1 cells assessed as reduction in ERK phosphorylation at T202//Y204 residues at 20 to 80 nM after 1 hr by Western blot analysis	29288940
NCI-H3122	Function assay		Inhibition of ALK phosphorylation at Y1278 residue in human NCI-H3122 cells at 20 to 80 nM after 1 hr by Western blot analysis	29288940
NCI-H3122	Function assay		Inhibition of ALK in human NCI-H3122 cells assessed as reduction in STAT3 phosphorylation at Y705 residue at 20 to 80 nM after 1 hr by Western blot analysis	29288940
NCI-H3122	Function assay		Inhibition of ALK in human NCI-H3122 cells assessed as reduction in Akt phosphorylation at S473 residue at 20 to 80 nM after 1 hr by Western blot analysis	29288940
NCI-H3122	Function assay		Inhibition of ALK in human NCI-H3122 cells assessed as reduction in ERK phosphorylation at T202//Y204 residues at 20 to 80 nM after 1 hr by Western blot analysis	29288940
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Informations chimiques, stockage et stabilité

Poids moléculaire	406.41	Formule	C₂₁H₁₉FN₆O₂	Stockage (À partir de la date de réception)	3 ans-20°Cpoudre
N° CAS	1454846-35-5	Télécharger le SDF		Stockage des solutions mères	1 an-80°Cen solvant 1 mois-20°Cen solvant
Synonymes	N/A			Smiles	CC1C2=C(C=CC(=C2)F)C(=O)N(CC3=NN(C(=C3C4=CC(=C(N=C4)N)O1)C#N)C)C

Solubilité

In vitro
Lot:

DMSO : 81 mg/mL (199.3 mM)
(Le DMSO contaminé par lhumidité peut réduire la solubilité. Utiliser du DMSO frais et anhydre.)

Ethanol : 40.5 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.
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 Validé par les laboratoires Selleck. Si vous avez besoin dajustements à cette formulation, contactez notre équipe de vente pour des tests personnalisés.	4.000mg/ml (9.84mM)	Taking the 1 mL working solution as an example, add 50 μL of 80 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 clarify; 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.
Clear solution	5% DMSO 1 95% Corn oil Validé par les laboratoires Selleck. Si vous avez besoin dajustements à cette formulation, contactez notre équipe de vente pour des tests personnalisés.	0.400mg/ml (0.98mM)	Taking the 1 mL working solution as an example, add 50 μL of 8 mg/ml clear DMSO stock solution to 950 μL of corn oil and mix evenly. 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.

Calculateur de formulation in vivo (Solution claire)

Étape 1 : Entrez 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 : Entrez la formulation in vivo (Ceci nest que 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, ajouter ensuiteμL PEG300, mélanger et clarifier, ajouter ensuiteμL Tween 80, mélanger et clarifier, ajouter ensuite μL ddH₂O, mélanger et clarifier.

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

Remarque : 1. Assurez-vous 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 peuvent être utilisées pour faciliter la dissolution.

Mécanisme daction

Targets/IC₅₀/Ki	ROS1 (Cell-free assay) <0.02 nM(Ki) ALK (Cell-free assay) <0.07 nM(Ki) ALK (L1196M) (Cell-free assay) 0.07 nM(Ki) LTK (TYK1) (Cell-free assay) 2.7 nM FER (Cell-free assay) 3.3 nM FES (FPS) (Cell-free assay) 6 nM PTK2B (FAK2) (Cell-free assay) 14 nM TNK2 (ACK) (Cell-free assay) 17 nM PTK2 (FAK) (Cell-free assay) 17 nM NTRK2 (TRKB) (Cell-free assay) 23 nM NTRK1 (TRKA) (Cell-free assay) 24 nM NTRK3 (TRKC) (Cell-free assay) 46 nM FRK (PTK5) (Cell-free assay) 53 nM EGFR (ErbB1) T790M L858R (Cell-free assay) 245 nM
In vitro	PF-06463922 démontre une activité cellulaire significative contre ALK et un large éventail de mutations cliniques d'ALK avec des IC50 allant de 0.2 nM à 77 nM. PF-06463922 inhibe significativement la prolifération cellulaire et induit l'apoptose cellulaire dans les cellules humaines de CPNPC HCC78 hébergeant des fusions SLC34A2-ROS1 et les cellules BaF3-CD74-ROS1 exprimant le CD74-ROS1 humain. PF-06463922 montre également une puissante activité inhibitrice de croissance et induit l'apoptose dans les cellules de CPNPC hébergeant des fusions ALK non mutantes ou mutantes.
In vivo	Chez les rats, le PF-06463922 présente une faible clairance plasmatique, un volume de distribution modéré, une demi-vie raisonnable, une faible propension à l'efflux médiatisé par la p-glycoprotéine 1 et une biodisponibilité de 100%. In vivo, le PF-06463922 montre une efficacité antitumorale cytoréductrice dans les modèles de xénogreffes NIH3T3 exprimant le CD74-ROS1 humain et Fig-ROS1 via l'inhibition de la phosphorylation de ROS1 et des molécules de signalisation en aval, ainsi que l'inhibition de la protéine du cycle cellulaire Cycline D1 dans les tumeurs. In vivo, le PF-06463922 démontre également une activité antitumorale marquée chez les souris porteuses de xénogreffes tumorales exprimant EML4-ALK, EML4-ALK-L1196M, EML4-ALK-G1269A, EML4-ALK-G1202R ou NPM-ALK.
Références	[1] https://pubmed.ncbi.nlm.nih.gov/24819116/ [2] http://mct.aacrjournals.org/content/12/11_Supplement/A277.short [3] http://mct.aacrjournals.org/content/12/11_Supplement/C253.short

Applications

Méthodes	Biomarqueurs	Images	PMID
Western blot	p-ALK / ALK		29650534

Informations sur lessai clinique

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

Numéro NCT	Recrutement	Conditions	Sponsor/Collaborateurs	Date de début	Phases
NCT06378892	Recruiting	Non Small Cell Lung Cancer Metastatic\|ALK Gene Mutation	Centro di Riferimento Oncologico - Aviano	March 15 2024	Phase 2
NCT06092086	Recruiting	ALK Positive Non-small Cell Lung Cancer	Guangdong Association of Clinical Trials	August 18 2023	Phase 2
NCT05297890	Active not recruiting	Advanced or Metastatic ROS1-Positive Non-Small Cell Lung Cancer	CStone Pharmaceuticals\|Pfizer	May 27 2022	Phase 2
NCT05224609	Recruiting	Moderate Hepatic Impairment\|Severe Hepatic Impairment\|Healthy Volunteers	Pfizer	April 28 2022	Phase 1

Support technique

Instructions de manipulation

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

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Questions fréquemment posées

Question 1:
Do you have any special suggestions for solution of S7536 to be applied to mouse models?

Réponse :
For S7536, we recommend 2% DMSO+30% PEG 300+ddH2O (up to 5mg/ml) for its in vivo application.

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Structure chimique

Poids moléculaire: 406.41