Lorlatinib (PF-6463922) ALK inibitore

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Controllo Qualità

Lotto: Purezza: 99.95%

99.95

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

Coltura cellulare, trattamento e concentrazione di lavoro

Linee cellulari	Tipo di saggio	Tempo di incubazione	Descrizione dellattività	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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Informazioni chimiche, conservazione e stabilità

Peso molecolare	406.41	Formula	C₂₁H₁₉FN₆O₂	Conservazione (Dalla data di ricezione)	3 anni-20°Cpolvere
N. CAS	1454846-35-5	Scarica SDF		Conservazione delle soluzioni stock	1 anno-80°Cin solvente 1 mese-20°Cin solvente
Sinonimi	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

Solubilità

In vitro
Lotto:

DMSO : 81 mg/mL (199.3 mM)
(Il DMSO contaminato da umidità può ridurre la solubilità. Utilizzare DMSO fresco e anidro.)

Ethanol : 40.5 mg/mL

Water : Insoluble

Calcolatore di Molarità

Massa	Concentrazione	Volume	Peso molecolare
=	×	×

Calcolatore di Diluizione Calcolatore del Peso Molecolare

In vivo Lotto:
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 Validato dai laboratori Selleck. Se necessiti di modifiche a questa formulazione, contatta il nostro team di vendita per test personalizzati.	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 Validato dai laboratori Selleck. Se necessiti di modifiche a questa formulazione, contatta il nostro team di vendita per test personalizzati.	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.

Calcolatore di formulazione in vivo (Soluzione chiara)

Passo 1: Inserire le informazioni di seguito (Consigliato: Un animale aggiuntivo per tenere conto della perdita durante lesperimento)

Dosaggio: mg/kg Peso medio degli animali: g Volume di dosaggio per animale:μL Numero di animali:

Passo 2: Inserire la formulazione in vivo (Questo è solo il calcolatore, non la formulazione. Contattateci prima se non cè una formulazione in vivo nella sezione Solubilità.)

% DMSO + % + % Tween 80 + % ddH₂O

%DMSO+ %

Risultati del calcolo:

Concentrazione di lavoro: mg/ml;

Metodo per preparare il liquido master di DMSO: mg farmaco predissolto in μL DMSO ( Concentrazione del liquido master mg/mL, Vi preghiamo di contattarci prima se la concentrazione supera la solubilità del DMSO del lotto del farmaco. )

Metodo per preparare la formulazione in vivo: Prendere μL DMSO liquido master, quindi aggiungereμL PEG300, mescolare e chiarire, quindi aggiungereμL Tween 80, mescolare e chiarire, quindi aggiungere μL ddH₂O, mescolare e chiarire.

Metodo per preparare la formulazione in vivo: Prendere μL DMSO liquido master, quindi aggiungere μL Olio di mais, mescolare e chiarire.

Nota: 1. Si prega di assicurarsi che il liquido sia limpido prima di aggiungere il solvente successivo.
2. Assicurarsi di aggiungere il/i solvente/i in ordine. È necessario assicurarsi che la soluzione ottenuta, nellaggiunta precedente, sia una soluzione limpida prima di procedere allaggiunta del solvente successivo. Metodi fisici come il vortex, gli ultrasuoni o il bagno dacqua calda possono essere utilizzati per facilitare la dissoluzione.

Meccanismo dazione

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 dimostra una significativa attività cellulare contro ALK e un ampio set di mutazioni cliniche di ALK con IC50 che vanno da 0,2 nM a 77 nM. PF-06463922 inibisce significativamente la proliferazione cellulare e induce l'apoptosi cellulare nelle cellule umane di NSCLC HCC78 che ospitano fusioni SLC34A2-ROS1 e nelle cellule BaF3-CD74-ROS1 che esprimono CD74-ROS1 umano. PF-06463922 mostra anche una potente attività inibitoria della crescita e induce l'apoptosi nelle cellule di NSCLC che ospitano fusioni ALK non mutanti o mutanti.
In vivo	Nei ratti, PF-06463922 mostra una bassa clearance plasmatica, un moderato volume di distribuzione, una ragionevole emivita, una bassa propensione all'efflusso mediato dalla p-glicoproteina 1 e una biodisponibilità del 100%. In vivo, PF-06463922 mostra un'efficacia antitumorale citoreduciva nei modelli di xenotrapianto NIH3T3 che esprimono CD74-ROS1 umano e Fig-ROS1 tramite l'inibizione della fosforilazione di ROS1 e delle molecole di segnalazione a valle, nonché l'inibizione della proteina del ciclo cellulare Ciclina D1 nei tumori. In vivo, PF-06463922 dimostra anche una marcata attività antitumorale nei topi portatori di xenotrapianti tumorali che esprimono EML4-ALK, EML4-ALK-L1196M, EML4-ALK-G1269A, EML4-ALK-G1202R o NPM-ALK.
Riferimenti	[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

Applicazioni

Metodi	Biomarcatori	Immagini	PMID
Western blot	p-ALK / ALK		29650534

Informazioni sullo studio clinico

(dati da https://clinicaltrials.gov, aggiornato il 2024-05-22)

Numero NCT	Reclutamento	Condizioni	Sponsor/Collaboratori	Data di inizio	Fasi
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

Supporto tecnico

Istruzioni per la manipolazione

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

Per qualsiasi altra domanda, si prega di lasciare un messaggio.

Domande Frequenti

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

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

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Struttura chimica

Peso molecolare: 406.41