Loratinib (PF-06463922; Lorlatinib; lorbrena)

Alias: Lorbrena; PF06463922; PF-6463922; PF6463922; PF 6463922; PF 06463922; PF-06463922; Loratinib
Cat No.:V0613 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.
Loratinib (PF-06463922; Lorlatinib; lorbrena) Chemical Structure CAS No.: 1454846-35-5
Product category: ALK
This product is for research use only, not for human use. We do not sell to patients.
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Other Forms of Loratinib (PF-06463922; Lorlatinib; lorbrena):

  • PF-06463922 (Loratinib) acetate
Official Supplier of:
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Purity & Quality Control Documentation

Purity: ≥98%

Product Description

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.

Biological Activity I Assay Protocols (From Reference)
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)
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]
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]
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.
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.
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.
References

[1]. J Med Chem . 2014 Jun 12;57(11):4720-44.

[2].Mol Cancer Ther (2013) 12 (11_Supplement): A277.

[3]. Mol Cancer Ther (2013) 12 (11_Supplement): C253.

These protocols are for reference only. InvivoChem does not independently validate these methods.
Physicochemical Properties
Molecular Formula
C21H19FN6O2
Molecular Weight
406.41
Exact Mass
406.16
Elemental Analysis
C, 62.06; H, 4.71; F, 4.67; N, 20.68; O, 7.87
CAS #
1454846-35-5
Appearance
White to off-white solid powder
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
InChi Key
IIXWYSCJSQVBQM-LLVKDONJSA-N
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
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
Synonyms
Lorbrena; PF06463922; PF-6463922; PF6463922; PF 6463922; PF 06463922; PF-06463922; Loratinib
HS Tariff Code
2934.99.09.01
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)
Solubility Data
Solubility (In Vitro)
DMSO: ~81 mg/mL (~199.3 mM)
Water: <1 mg/mL
Ethanol: ~30 mg/mL warmed (~73.8 mM)
Solubility (In Vivo)
2% DMSO+30% PEG 300+ddH2O: 5mg/mL (Please use freshly prepared in vivo formulations for optimal results.)
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.

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Note: Chemical formula is case sensitive: C12H18N3O4  c12h18n3o4
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In vivo Formulation Calculator (Clear solution)
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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.
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Clinical Trial Information
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
Biological Data
  • Loratinib (PF-06463922)

    PF-06463922 is a potent inhibitor of ROS1.. 2015 Mar 17; 112(11): 3493–3498.

  • Loratinib (PF-06463922)

    PF-06463922 inhibits crizotinib-induced ROS1 mutants.. 2015 Mar 17; 112(11): 3493–3498.

  • Loratinib (PF-06463922)

    (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.. 2015 Mar 17; 112(11): 3493–3498.

  • Loratinib (PF-06463922)

    PF-06463922 inhibits ROS1 fusion-driven tumorigenesis in vivo.. 2015 Mar 17; 112(11): 3493–3498.

  • Loratinib (PF-06463922)

    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.. 2015 Mar 17; 112(11): 3493–3498.

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