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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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| ADME/Pharmacokinetics |
Absorption, Distribution and Excretion
Following a single oral dose of 100 mg lorlatinib, the median time to peak concentration (Tmax) was 1.2 hours (0.5 to 4 hours); after steady-state with a once-daily oral dose of 100 mg, the median time to peak concentration was 2 hours (0.5 to 23 hours). The mean absolute bioavailability after oral administration was 81% (90% CI 75.7%, 86.2%) compared to intravenous administration. Concomitant administration of lorlatinib with a high-fat, high-calorie meal (approximately 1000 calories, of which 150 calories are from protein, 250 calories from carbohydrates, and 500 to 600 calories from fat) had no clinically significant effect on the pharmacokinetics of lorlatinib. Following a single oral dose of 100 mg of radiolabeled lorlatinib, 48% of the radioactive material was recovered in the urine (<1% unchanged) and 41% was recovered in the feces (approximately 9% unchanged). After a single intravenous administration, the mean (CV%) steady-state volume of distribution (Vss) was 305 L (28%). After a single oral 100 mg dose, the mean oral clearance (CL/F) was 11 L/h (35%), increasing to 18 L/h (39%) at steady state, suggesting self-induction. Metabolism/MetabolitesIn vitro studies showed that lorlatinib is primarily metabolized by CYP3A4 and UGT1A4, with less metabolic activity via CYP2C8, CYP2C19, CYP3A5, and UGT1A3. In plasma, the benzoic acid metabolite (M8) generated by the oxidative cleavage of lorlatinib's amide and aromatic ether bonds accounted for 21% of circulating radioactivity in human [14C] mass balance studies. This oxidative cleavage metabolite M8 has no pharmacological activity. Biological half-life After a single oral dose of 100 mg lorlatinib, the mean plasma half-life (t½) is 24 hours (40%). |
| Toxicity/Toxicokinetics |
Hepatotoxicity
In early large clinical trials, up to 28% of patients receiving standard-dose lorlatinib experienced elevated serum transaminase levels, but only 2% had transaminase levels exceeding 5 times the upper limit of normal, rarely leading to early discontinuation. These abnormalities were usually transient, asymptomatic, and without jaundice. No clinically significant liver injury cases were observed in premarket clinical trials. In contrast, most other ALK inhibitors are associated with cases of acute liver injury, which can be severe and even fatal. Liver injury typically occurs within 4 to 12 weeks of starting treatment, manifesting as a significant increase in serum transaminase levels, followed by jaundice and progressive liver dysfunction. While lorlatinib has not been found to be associated with severe liver injury, its clinical application is limited. Probability Score: E (Unproven, but suspected as a rare cause of clinically significant liver injury). Effects during pregnancy and lactation ◉ Overview of use during lactation There is currently no information regarding the clinical use of lorlatinib during lactation. The manufacturer recommends discontinuing breastfeeding during lorlatinib treatment and for 7 days after the last dose. ◉ Effects on breastfed infants As of the revision date, no relevant published information was found. ◉ Effects on lactation and breast milk As of the revision date, no relevant published information was found. Protein binding In vitro studies showed that lorlatinib binds to plasma proteins in 66% at a concentration of 2.4 µM. The blood-to-plasma ratio was 0.99. |
| References | |
| Additional Infomation |
Pharmacodynamics
Based on data from the B7461001 study, an exposure-response relationship was observed for grade 3 or 4 hypercholesterolemia and any grade 3 or 4 adverse events at steady-state exposure at the recommended dose. The probability of adverse events increased with increasing lorlatinib exposure. In the same B7461001 study, among 295 patients receiving the recommended once-daily dose of 100 mg lorlatinib and undergoing ECG monitoring, the maximum mean change in PR interval from baseline was 16.4 ms (upper limit of the two-sided 90% confidence interval [CI] 19.4 ms). Among 284 patients with a baseline PR interval <200 ms, 14% experienced a PR interval prolongation ≥200 ms after initiation of lorlatinib. PR interval prolongation was concentration-dependent, and atrioventricular block occurred in 1% of patients. Finally, in the activity assessment portion of the B7461001 study, no significant mean prolongation of the QTcF interval (i.e., >20 ms) was detected in the 275 patients treated with the recommended dose of lorlatinib. |
| Molecular Formula |
C21H19FN6O2
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|---|---|
| Molecular Weight |
406.41
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| Exact Mass |
406.155
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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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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
0
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| Heavy Atom Count |
30
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| Complexity |
700
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| Defined Atom Stereocenter Count |
1
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| SMILES |
FC1C([H])=C([H])C2C(N(C([H])([H])[H])C([H])([H])C3C(=C(C#N)N(C([H])([H])[H])N=3)C3C([H])=NC(=C(C=3[H])O[C@]([H])(C([H])([H])[H])C=2C=1[H])N([H])[H])=O
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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.
Analysis of the Effectiveness and Safety of Lorlatinib in Untreated ALK-Positive NSCLC Patients in a French Real-World Context
CTID: NCT06487078
Phase: N/A Status: Not yet recruiting
Date: 2024-11-08
PF-06463922 is a potent inhibitor of ROS1.Proc Natl Acad Sci U S A. 2015 Mar 17; 112(11): 3493–3498. |
PF-06463922 inhibits crizotinib-induced ROS1 mutants.Proc Natl Acad Sci U S A. 2015 Mar 17; 112(11): 3493–3498. |
(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. |
PF-06463922 inhibits ROS1 fusion-driven tumorigenesis in vivo.Proc Natl Acad Sci U S A. 2015 Mar 17; 112(11): 3493–3498. |
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. |
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