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Lorlatinib (PF-6463922)

Catalog No.S7536 Purity:99.95%

Lorlatinib (PF-6463922) is a potent, dual ALK/ROS1 inhibitor with K_i of <0.02 nM, <0.07 nM, and 0.7 nM for ROS1, ALK (WT), and ALK (L1196M), respectively. PF-06463922 induces apoptosis. Phase 1.

Lorlatinib (PF-6463922) Chemical Structure

CAS No. 1454846-35-5

Purity & Quality Control

Batch: Purity: 99.95%

99.95

Lorlatinib (PF-6463922) Related Products

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Signaling Pathway

ALK Signaling Pathway

Cell Data

Cell Lines	Assay Type	Incubation Time	Activity Description	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
Click to View More Cell Line Experimental Data

Biological Activity

Description

Targets

ROS1 ^[1] (Cell-free assay)	ALK ^[1] (Cell-free assay)	ALK (L1196M) ^[1] (Cell-free assay)	LTK (TYK1) ^[1] (Cell-free assay)	FER ^[1] (Cell-free assay)	Click to View More Targets
<0.02 nM(Ki)	<0.07 nM(Ki)	0.07 nM(Ki)	2.7 nM	3.3 nM	Click to View More Targets

In vitro
In vitro	PF-06463922 demonstrates significant cell activity against ALK and a large set of ALK clinical mutations with IC50 ranging from 0.2 nM-77 nM. ^[1] PF-06463922 significantly inhibits cell proliferation and induces cell apoptosis in the HCC78 human NSCLC cells harboring SLC34A2-ROS1 fusions and the BaF3-CD74-ROS1 cells expressing human CD74-ROS1.^[2] PF-06463922 also shows potent growth inhibitory activity and induces apoptosis in the NSCLC cells harboring either non-mutant ALK or mutant ALK fusions. ^[3]
Experimental Result Images	Methods	Biomarkers	Images	PMID
Experimental Result Images	Western blot	p-ALK / ALK		29650534

In Vivo
In vivo	In rats, PF-06463922 displays low plasma clearance, a moderate volume of distribution, a reasonable half-life, low propensity for p-glycoprotein 1-mediated efflux and a bioavailability of 100%. ^[1] In vivo, PF-06463922 shows cytoreductive antitumor efficacy in the NIH3T3 xenograft models expressing human CD74-ROS1 and Fig-ROS1 via inhibition in ROS1 phosphorylation and the downstream signaling molecules, as well as inhibition of the cell cycle protein Cyclin D1 in tumors. ^[2] In vivo, PF-06463922 also demonstrates marked antitumor activity in mice bearing tumor xenografts expressing EML4-ALK, EML4-ALK-L1196M, EML4-ALK-G1269A, EML4-ALK-G1202R or NPM-ALK. ^[3]

NCT Number	Recruitment	Conditions	Sponsor/Collaborators	Start Date	Phases
Clinical Trial Information (data from https://clinicaltrials.gov, updated on 2024-05-22)
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

References
[1] Johnson TW, et al. J Med Chem. 2014, 57(11), 4720-4744. [2] Zou HY, et al. Mol Cancer Ther. 2013, 12, A277. [3] Zou HY, et al. Mol Cancer Ther. 2013, 12, C253.

References

Chemical Information & Solubility

Molecular Weight	406.41	Formula	C₂₁H₁₉FN₆O₂
CAS No.	1454846-35-5	SDF	Download Lorlatinib (PF-6463922) SDF
Smiles	CC1C2=C(C=CC(=C2)F)C(=O)N(CC3=NN(C(=C3C4=CC(=C(N=C4)N)O1)C#N)C)C
Storage (From the date of receipt)	3 years-20°Cpowder	Storage of Stock Solutions Aliquot the stock solutions to avoid repeated freeze-thaw cycles	1 year-80°Cin solvent
Storage (From the date of receipt)	3 years-20°Cpowder		1 month-20°Cin solvent

In vitro
Batch:

DMSO : 81 mg/mL ( (199.3 mM) Moisture-absorbing DMSO reduces solubility. Please use fresh DMSO.)

Ethanol : 40.5 mg/mL

Water : Insoluble

Molecular Weight Calculator

In vivo Batch: Add solvents to the product individually and in order.				In vivo Formulation Calculator
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 Validated by Selleck labs. Should you need adjustments to this formulation, contact our sales team for custom testing.	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 Validated by Selleck labs. Should you need adjustments to this formulation, contact our sales team for custom testing.	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.

Preparing Stock Solutions

Molarity Calculator

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Dilution Calculator Molecular Weight Calculator

In vivo Formulation Calculator (Clear solution)

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Method for preparing DMSO master liquid: mg drug pre-dissolved in μL DMSO ( Master liquid concentration mg/mL, Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug. )

Method for preparing in vivo formulation: Take μL DMSO master liquid, next addμL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH₂O, mix and clarify.

Method for preparing in vivo formulation: Take μL DMSO master liquid, next add μL Corn oil, mix and clarify.

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Tech Support

Answers to questions you may have can be found in the inhibitor handling instructions. Topics include how to prepare stock solutions, how to store inhibitors, and issues that need special attention for cell-based assays and animal experiments.

Handling Instructions

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Frequently Asked Questions

Question 1:
Do you have any special suggestions for solution of S7536, Lorlatinib (PF-6463922) to be applied to mouse models?

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

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