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5mg |
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10mg |
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25mg |
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50mg |
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100mg |
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250mg |
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Purity: ≥98%
Loratinib (formerly also known as Lorlatinib, PF-06463922; trade name:Lorbrena) is a potent, orally bioavailable, brain-penetrant,ATP-competitive, anddual ALK/ROS1 inhibitor with potential antitumor activity. With Ki values of less than 0.02 nM, 0.07 nM, and 0.7 nM, respectively, it inhibits ROS1, ALK (WT), and ALK (L1196M).The FDA approved loratinib for the treatment of patients with metastatic non-small cell lung cancer that is positive for anaplastic lymphoma kinase (ALK). After being administered, PF-06463922 binds to and inhibits ROS1 kinases as well as ALK kinases. This disrupts ALK and ROS1-mediated signaling and ultimately stops tumor cell growth. In addition to treating ROS1 fusion-positive cancers, including those that need drugs with CNS-penetrating capabilities, PF-06463922 may be able to reverse the effects of crizotinib resistance caused by ROS1 mutation.
Targets |
ALKL1196 (IC50 = 15-43 nM); ALKG1269A (IC50 = 14-80 nM); ALK1151Tins (IC50 = 38-50 nM); ALKG1202R (IC50 = 77-113 nM); ALKWT (IC50 <0.07 nM); ALKL1996M (IC50 = 0.6 nM); ALKG1269A (IC50 = 0.9 nM); ALK1151Tins (IC50 = 0.1 nM); ALKL1152R (IC50 <0.1 nM); ALKS1206Y (IC50 = 0.2 nM); ALKC1156Y (IC50 <0.1 nM); ALKF1174L (IC50 <0.1nM)
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ln Vitro |
PF-06463922 exhibits a broad range of ALK clinical mutations with IC50 values between 0.2 and 77 nM, as well as notable cell activity against ALK. [1] In HCC78 human NSCLC cells carrying SLC34A2-ROS1 fusions and BaF3-CD74-ROS1 cells expressing human CD74-ROS1, PF-06463922 dramatically reduces cell proliferation and induces cell apoptosis. **[2]** In NSCLC cells expressing either non-mutant ALK or mutant ALK fusions, PF-06463922 also exhibits strong growth inhibitory activity and causes apoptosis.[3]
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ln Vivo |
PF-06463922 exhibits a low propensity for p-glycoprotein 1-mediated efflux, a moderate volume of distribution, a reasonable half-life, low plasma clearance, and 100% bioavailability in rats.[1] PF-06463922 exhibits cytoreductive antitumor efficacy in NIH3T3 xenograft models that express human CD74-ROS1 and Fig-ROS1 through the inhibition of downstream signaling molecules and ROS1 phosphorylation, in addition to inhibiting the cell cycle protein Cyclin D1 in tumors.[2] In mice with tumor xenografts expressing EML4-ALK, EML4-ALK-L1196M, EML4-ALK-G1269A, EML4-ALK-G1202R, or NPM-ALK, PF-06463922 also exhibits strong antitumor activity in vivo.[3]
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Enzyme Assay |
Microfluidic mobility shift assay is used to measure kinase activity in recombinant human wild-type and mutant ALK kinase domain proteins (amino acids 1093–1411), which are produced in-house via baculoviral expression and autophosphorylation with MgATP. The reactions contained 3 μM 5-FAM-KKSRGDYMTMQIG-CONH2), 5 mM MgCl2, 1.3 nM wild-type ALK or 0.5 nM mutant ALK (suitable to produce 15-20% phosphorylation of peptide substrate after 1 hour of reaction), and the Kmlevel of ATP in 25 mM Hepes, pH 7.1. The results of kinetic and crystallographic investigations demonstrate that the inhibitors are ATP-competitive. Fitting the conversion (%) to a competitive inhibition equation yields the Kivalues. The procedure for assaying ROS1 enzyme is the same as that for ALK, with the exception that 0.25 nM recombinant human ROS1 catalytic domain (amino acids 1883-2347) is used. A 206-kinase panel is utilized to assess the selectivity of kinase inhibitors.
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Cell Assay |
In 96-well plates, cells are sown in growth medium with 10% FBS, and they are incubated at 37°C for the entire night. The cells are incubated at 37°C for 72 hours after serial dilutions of Lorlatinib or suitable controls are added to the assigned wells the following day. To ascertain the relative cell numbers, a CellTiter-Glo assay is conducted. A four-parameter analytical method is used to fit a concentration-response curve and determine IC50 values.
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Animal Protocol |
In LSL-FIG-ROS1;Cdkn2a−/−;LSL-Luc mice, de novoGBM tumorigenesis is induced by intracranial stereotactic injections of Adeno-Cre, as previously reported. BLI is used to track the development of tumors as will be discussed below. Animals are randomly assigned to either vehicle control or 3-, 7-, or 14-day treatments with the prescribed doses of lerlatinib once tumors reach a specific size (107 p -1·s -1·cm -2·sr -1). The medication is delivered via s.c. implanted Alzet osmotic pumps. Following therapy, GBM tumors are microdissected, tissues are flash-frozen in liquid N2, and mice are killed. For histology, the remaining brains are processed.
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References | |
Additional Infomation |
Lorlatinib is a cyclic ether that is 16,17-dihydro-2H-8,4-(metheno)pyrazolo[4,3-h][2,5,11]benzoxadiazacyclotetradecin-15(10H)-one substituted by methyl groups at positions 2 and 10R, and by cyano, amino and fluoro groups at positions 3, 7 and 12 respectively. It is a small molecule inhibitor of ALK and ROS1 kinase developed by Pfizer for the treatment of ALK-positive non-small cell lung cancer. It has a role as an antineoplastic agent and an EC 2.7.10.1 (receptor protein-tyrosine kinase) inhibitor. It is a member of pyrazoles, a member of monofluorobenzenes, an aromatic ether, a nitrile, a member of benzamides, an azamacrocycle, an aminopyridine, a cyclic ether and an organic heterotetracyclic compound.
Lorlatinib is a third-generation ALK tyrosine kinase inhibitor (TKI) for patients with ALK-positive metastatic non-small cell lung cancer which was first approved by the US FDA in November of 2018. It was subsequently approved by the EMA in 2019 for the treatment of select patients with previously treated advanced ALK-positive non-small cell lung cancer, followed by an expanded approval in 2022 to include lorlatinib as a first-line treatment option in advanced ALK-positive NSCLC. Lorlatinib is a Kinase Inhibitor. The mechanism of action of lorlatinib is as a Kinase Inhibitor, and Cytochrome P450 3A Inducer, and P-Glycoprotein Inducer, and Cytochrome P450 2B6 Inducer, and Organic Cation Transporter 1 Inhibitor, and Organic Anion Transporter 3 Inhibitor, and Multidrug and Toxin Extrusion Transporter 1 Inhibitor, and Breast Cancer Resistance Protein Inhibitor. View More
Lorlatinib is a selective tyrosine kinase receptor inhibitor used in the therapy of selected cases of advanced non-small cell lung cancer. Lorlatinib is associated with transient elevations in serum aminotransferase levels during treatment but has not been linked to instances of clinically apparent acute liver injury that have been described with other similar kinase inhibitors.
Lorlatinib is indicated for the treatment of adult patients with ALK-positive metastatic non-small cell lung cancer (NSCLC). In the EU, it is indicated for the treatment of adult patients with ALK-positive advanced NSCLC not previously treated with an ALK inhibitor, or whose disease has progressed after using either [alectinib] or [ceritinib], or [crizotinib] and at least one other ALK inhibitor. Lorviqua as monotherapy is indicated for the treatment of adult patients with anaplastic lymphoma kinase (ALK)â��positive advanced nonâ��small cell lung cancer (NSCLC) previously not treated with an ALK inhibitor. Lorviqua as monotherapy is indicated for the treatment of adult patients with ALKâ��positive advanced NSCLC whose disease has progressed after: alectinib or ceritinib as the first ALK tyrosine kinase inhibitor (TKI) therapy; orcrizotinib and at least one other ALK TKI. Lorlatinib is a selective tyrosine kinase receptor inhibitor used in the therapy of selected cases of advanced non-small cell lung cancer. Lorlatinib is associated with transient elevations in serum aminotransferase levels during treatment but has not been linked to instances of clinically apparent acute liver injury that have been described with other similar kinase inhibitors. Based on data from Study B7461001, exposure-response relationships for Grade 3 or 4 hypercholesterolemia and for any Grade 3 or 4 adverse reaction were observed at steady-state exposures achieved at the recommended dosage, with higher probability of the occurrence of adverse reactions with increasing lorlatinib exposure. In 295 patients who received lorlatinib at the recommended dosage of 100 mg once daily and had an ECG measurement in the same Study B7461001, the maximum mean change from baseline for their PR interval was 16.4 ms (2-sided 90% upper confidence interval [CI] 19.4 ms). Among the 284 patients with PR interval <200 ms at baseline, 14% had PR interval prolongation ≥200 ms after starting use with lorlatinib. The prolongation of PR interval occurred in a concentration-dependent manner and atrioventricular block occurred in 1% of patients. Finally, in 275 patients who received lorlatinib at the recommended dosage in the activity-estimating portion of Study B7461001, no large mean increases from baseline in the QTcF interval (i.e., >20 ms) were detected. Absorption: The median lorlatinib Tmax was 1.2 hours (0.5 to 4 hours) following a single oral 100 mg dose and 2 hours (0.5 to 23 hours) following 100 mg orally once daily at steady state. The mean absolute bioavailability is 81% (90% CI 75.7%, 86.2%) after oral administration compared to intravenous administration. Administration of lorlatinib with a high fat, high-calorie meal (approximately 1000 calories with 150 calories from protein, 250 calories from carbohydrate, and 500 to 600 calories from fat) had no clinically meaningful effect on lorlatinib pharmacokinetics. The mean plasma half-life (t½) of lorlatinib was 24 hours (40%) after a single oral 100 mg dose of lorlatinib. |
Molecular Formula |
C21H19FN6O2
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Molecular Weight |
406.41
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Exact Mass |
406.16
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Elemental Analysis |
C, 62.06; H, 4.71; F, 4.67; N, 20.68; O, 7.87
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CAS # |
1454846-35-5
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Related CAS # |
1924207-18-0 (acetate);2135926-03-1;1454846-35-5;2306217-6 (hydrate);
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PubChem CID |
71731823
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Appearance |
White to off-white solid powder
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Density |
1.4±0.1 g/cm3
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Boiling Point |
675.0±55.0 °C at 760 mmHg
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Flash Point |
362.1±31.5 °C
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Vapour Pressure |
0.0±2.1 mmHg at 25°C
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Index of Refraction |
1.687
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LogP |
1.24
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tPSA |
110.06
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SMILES |
C[C@@H]1C2=C(C=CC(=C2)F)C(=O)N(CC3=NN(C(=C3C4=CC(=C(N=C4)N)O1)C#N)C)C
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InChi Key |
IIXWYSCJSQVBQM-LLVKDONJSA-N
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InChi Code |
InChI=1S/C21H19FN6O2/c1-11-15-7-13(22)4-5-14(15)21(29)27(2)10-16-19(17(8-23)28(3)26-16)12-6-18(30-11)20(24)25-9-12/h4-7,9,11H,10H2,1-3H3,(H2,24,25)/t11-/m1/s1
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Chemical Name |
(16R)-19-amino-13-fluoro-4,8,16-trimethyl-9-oxo-17-oxa-4,5,8,20-tetrazatetracyclo[16.3.1.02,6.010,15]docosa-1(22),2,5,10(15),11,13,18,20-octaene-3-carbonitrile
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Synonyms |
Lorbrena; PF06463922; PF-6463922; PF6463922; PF 6463922; PF 06463922; PF-06463922;Lorlatinib; 1454846-35-5; Lorbrena; Lorviqua; lorlatinibum; PF06463922
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HS Tariff Code |
2934.99.09.01
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Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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Solubility (In Vitro) |
DMSO: ~81 mg/mL (~199.3 mM)
Water: <1 mg/mL Ethanol: ~30 mg/mL warmed (~73.8 mM) |
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Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (6.15 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: 2.5 mg/mL (6.15 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C,1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (6.15 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. Solubility in Formulation 4: ≥ 2.5 mg/mL (6.15 mM) (saturation unknown) in 5% DMSO + 40% PEG300 + 5% Tween80 + 50% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. Preparation of 20% SBE-β-CD in Saline (4°C,1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. Solubility in Formulation 5: 2% DMSO+30% PEG 300+ddH2O: 5mg/mL |
Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
1 mM | 2.4606 mL | 12.3028 mL | 24.6057 mL | |
5 mM | 0.4921 mL | 2.4606 mL | 4.9211 mL | |
10 mM | 0.2461 mL | 1.2303 mL | 2.4606 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration: mg/mL;
Method for preparing DMSO stock solution: mg drug pre-dissolved in μL DMSO (stock solution 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 stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O,mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
NCT03126916 | Active Recruiting |
Drug: Busulfan Drug: Lorlatinib |
Ganglioneuroblastoma Neuroblastoma |
Children's Oncology Group | May 14, 2018 | Phase 3 |
NCT03909971 | Active Recruiting |
Drug: Lorlatinib | Carcinoma, Non-Small-Cell Lung | Pfizer | April 28, 2019 | Phase 2 |
NCT04362072 | Active Recruiting |
Drug: Lorlatinib | Carcinoma Non-Small-Cell Lung |
Pfizer | September 29, 2020 | Phase 4 |
NCT05144997 | Recruiting | Drug: Lorlatinib | Non-Small-Cell Lung Cancer NSCLC |
Pfizer | December 28, 2021 | Phase 4 |
NCT05948462 | Recruiting | Drug: Lorlatinib Drug: Pemetrexed |
Non-small Cell Lung Cancer Lung Cancer |
SCRI Development Innovations, LLC |
October 2023 | Phase 2 |
PF-06463922 is a potent inhibitor of ROS1.Proc Natl Acad Sci U S A. 2015 Mar 17; 112(11): 3493–3498. td> |
PF-06463922 inhibits crizotinib-induced ROS1 mutants.Proc Natl Acad Sci U S A. 2015 Mar 17; 112(11): 3493–3498. td> |
(A) Comparison of ROS1 crystal structures bound with PF-06463922 (green) and crizotinib (magenta). (B) PF-06463922 interactions with ROS1 and the PF-06463922 ROS1 binding site.Proc Natl Acad Sci U S A. 2015 Mar 17; 112(11): 3493–3498. td> |
PF-06463922 inhibits ROS1 fusion-driven tumorigenesis in vivo.Proc Natl Acad Sci U S A. 2015 Mar 17; 112(11): 3493–3498. td> |
PF-06463922 inhibits FIG-ROS1–mediated tumor growth in a model of GBM. (A) Representative photomicrographs of bioluminescent imaging of a mouse genetically engineered to develop a GBM and its response to a 7- and 14-d treatment with PF-06463922. (B) Decrease in BLI output 7 and 14 d post treatment.Proc Natl Acad Sci U S A. 2015 Mar 17; 112(11): 3493–3498. td> |