Lorlatinib (PF-6463922) ALK remmer

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Kwaliteitscontrole

Batch: Zuiverheid: 99.95%

99.95

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

Celkweek, behandeling & werkconcentratie

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

Chemische informatie, Opslag en Stabiliteit

Moleculair gewicht	406.41	Formule	C₂₁H₁₉FN₆O₂	Opslag (Vanaf de ontvangstdatum)	3 jaar-20°Cpoeder
CAS-nr.	1454846-35-5	SDF downloaden		Opslag van stamoplossingen	1 jaar-80°Cin oplosmiddel 1 maand-20°Cin oplosmiddel
Synoniemen	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

Oplosbaarheid

In vitro
Batch:

DMSO : 81 mg/mL (199.3 mM)
(Met vocht verontreinigde DMSO kan de oplosbaarheid verminderen. Gebruik verse, watervrije DMSO.)

Ethanol : 40.5 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.
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 Gevalideerd door Selleck labs. Mocht u aanpassingen aan deze formulering nodig hebben, neem dan contact op met ons verkoopteam voor aangepaste tests.	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 Gevalideerd door Selleck labs. Mocht u aanpassingen aan deze formulering nodig hebben, neem dan contact op met ons verkoopteam voor aangepaste tests.	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.

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	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 demonstreert significante celactiviteit tegen ALK en een grote set ALK klinische mutaties met IC50 variërend van 0.2 nM-77 nM. PF-06463922 remt significant de celproliferatie en induceert celapoptose in de HCC78 menselijke NSCLC-cellen met SLC34A2-ROS1 fusies en de BaF3-CD74-ROS1-cellen die menselijk CD74-ROS1 tot expressie brengen. PF-06463922 toont ook een potente groeiremmende activiteit en induceert apoptose in de NSCLC-cellen die ofwel niet-gemuteerde ALK of gemuteerde ALK-fusies herbergen.
In vivo	Bij ratten vertoont PF-06463922 een lage plasmaspeling, een matig verdelingsvolume, een redelijke halfwaardetijd, een lage neiging tot p-glycoproteïne 1-gemedieerde efflux en een biologische beschikbaarheid van 100%. In vivo toont PF-06463922 cytoreductieve antitumorwerkzaamheid in de NIH3T3 xenograftmodellen die menselijk CD74-ROS1 en Fig-ROS1 tot expressie brengen via remming van ROS1-fosforylering en de downstream signaalmoleculen, evenals remming van het celcyclusproteïne Cyclin D1 in tumoren. In vivo demonstreert PF-06463922 ook een duidelijke antitumoractiviteit bij muizen met tumorxenografts die EML4-ALK, EML4-ALK-L1196M, EML4-ALK-G1269A, EML4-ALK-G1202R of NPM-ALK tot expressie brengen.
Referenties	[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

Toepassingen

Methoden	Biomarkers	Afbeeldingen	PMID
Western blot	p-ALK / ALK		29650534

Informatie klinische proef

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

NCT-nummer	Rekrutering	Aandoeningen	Sponsor/Medewerkers	Startdatum	Fasen
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

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Veelgestelde vragen

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

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

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Chemische structuur

Moleculair gewicht: 406.41