Crizotinib (Xalkori; PF02341066)

Alias: PF-2341066; PF2341066; PF02341066; PF-02341066; PF 2341066; Crizotinib; PF 02341066; US trade name: Xalkori
Cat No.:V0590 Purity: =99.9%
Crizotinib (formerly known as PF-02341066; trade name: Xalkori) is a potent, orally bioavailable small molecule inhibitor of c-Met and ALK with potential anticancer activity.
Crizotinib (Xalkori; PF02341066) Chemical Structure CAS No.: 877399-52-5
Product category: c-MET
This product is for research use only, not for human use. We do not sell to patients.
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Other Forms of Crizotinib (Xalkori; PF02341066):

  • Crizotinib HCl
  • Crizotinib-d5 (PF-02341066-d5)
Official Supplier of:
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Top Publications Citing lnvivochem Products
InvivoChem's Crizotinib (Xalkori; PF02341066) has been cited by 1 publication
Purity & Quality Control Documentation

Purity: =99.87%

Purity: =99.9%

Product Description
Crizotinib (formerly known as PF-02341066; trade name: Xalkori) is a potent, orally bioavailable small molecule inhibitor of c-Met and ALK that is bioavailable when taken orally. In assays based on cells, it inhibits c-Met and ALK with IC50 values of 11 nM and 24 nM, respectively.
Biological Activity I Assay Protocols (From Reference)
Targets
ALK (IC50 = 20 nM); c-Met (IC50 = 8 nM)
ln Vitro
Crizotinib (PF-02341066) exhibits comparable efficacy (IC50 of 5 nM and 20 nM, respectively) against c-Met phosphorylation in mIMCD3 mouse or MDCK canine epithelial cells. When compared to NIH3T3 cells expressing the wild-type receptor, which has an IC50 of 13 nM, PF-2341066 exhibits better or comparable activity against cells engineered to express the c-Met ATP-binding site mutants V1092I or H1094R or the P-loop mutant M1250T, with IC50 values of 19 nM, 2 nM, and 15 nM, respectively. PF-2341066, on the other hand, exhibits a significant change in potency when compared to wild-type receptor when applied to cells that have been engineered to express the c-Met activation loop mutants Y1230C and Y1235D, with IC50 values of 127 nM and 92 nM, respectively. With IC50 values of 13 nM and 16 nM, respectively, PF-2341066 also effectively inhibits the phosphorylation of c-Met in NCI-H69 and HOP92 cells, which express the endogenous c-Met variants R988C and T1010I, respectively[1].
Crizotinib (PF-02341066) also potently inhibits NPM-ALK phosphorylation in Karpas299 or SU-DHL-1 ALCL cells with an IC50 of 24 nM. ALK-positive ALCL cells with an IC50 of 30 nM are capable of potently preventing cell proliferation, which is linked to G(1)-S-phase cell cycle arrest and induction of apoptosis, but not ALK-negative lymphoma cells[2].
ln Vivo
Crizotinib (PF-02341066) exhibits that both the 50 mg/kg/day and 75 mg/kg/day treatment cohorts have the potential to cause significant regression of large established tumors (> 600 mm3), with a 60% decrease in mean tumor volume over the 43-day administration schedule in the GTL-16 model. A different study shows that PF-2341066 can completely suppress GTL-16 tumor growth for longer than three months. During the course of the three-month treatment regimen at 50 mg/kg/day, only one out of twelve mice showed a discernible increase in tumor growth. In GTL-16 tumors, there is a notable dose-dependent decrease in CD31-positive endothelial cells at 12.5 mg/kg/day, 25 mg/kg/day, and 50 mg/kg/day. This suggests that MVD inhibition correlates with antitumor efficacy in a dose-dependent manner. In the GTL-16 and U87MG models, PF-2341066 exhibits a notable dose-dependent decrease in human VEGFA and IL-8 plasma levels. Phosphorylated c-Met, Akt, Erk, PLCλ1, and STAT5 levels are markedly inhibited in GTL-16 tumors after PF-2341066 is administered p.o.[1].
Treatment with 50 mg/kg PF-2341066 causes tumor regression in c-MET-amplified GTL-16 xenografts; this tumor regression is accompanied by a gradual decrease in 18F-FDG uptake and a reduction in the expression of GLUT-1, the glucose transporter[4].
Enzyme Assay
In 96-well plates, cells are seeded with media supplemented with 10% fetal bovine serum (FBS) and, after 24 hours, are transferred to serum-free media containing 0.04% bovine serum albumin (BSA). Related growth factors are added for up to 20 minutes in experiments looking into ligand-dependent RTK phosphorylation. Protein lysates are produced from cells after they are incubated with PF-2341066 for one hour and/or the appropriate ligands for the specified times. The cells are then once again washed with HBSS supplemented with one milligram of Na3VO4. After that, phosphorylation of particular protein kinases is evaluated by sandwich ELISA technique, which employs a detection antibody specific for phosphorylated tyrosine residues and specific capture antibodies used to coat 96-well plates. Protein lysates are added to antibody-coated plates and incubated for one night at 4°C. Next, the plates are rinsed seven times in 1% Tween 20 in PBS, then incubated for thirty minutes in a horseradish peroxidase-conjugated anti-total-phosphotyrosine (PY-20) antibody (1:500). Finally, the plates are rinsed seven times more. Finally, the plates are incubated in 3,3′,5,5′-tetramethyl benzidine peroxidase substrate to start a colorimetric reaction that is stopped by adding 0.09 N H2SO4 and (f) absorbance at 450 nm using a spectrophotometer.
Cell Assay
In low density, tumor cells are seeded in 96-well plates with growth media supplemented with 10% FBS.After 24 hours, the cells are moved to serum-free media containing 0.04% BSA and 0% FBS. Each well is filled with the appropriate controls or specified concentrations of PF-2341066, and the cells are incubated for a duration of 24 to 72 hours. After being seeded in 96-well plates with EGM2 media for 5 to 6 hours at a density of over 20,000 cells per well, human umbilical vascular endothelial cells (HUVEC) are overnight moved to serum-free medium. The next day, each well is filled with the appropriate controls or designated concentrations of PF-2341066. Following a one-hour incubation period, 100 ng/mL of HGF is added to the designated wells. To ascertain the relative tumor cell or HUVEC, a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay is conducted.
Animal Protocol
PF-2341066 is administered orally by gavage to athymic mice carrying xenografts (300-800 mm3) at predetermined dose levels. Mice are given PF-2341066 at predetermined intervals, and tumors are removed with humane care. Using a liquid nitrogen-cooled cryomortar and pestle, tumors are snap frozen, ground into a paste, protein lysates are produced, and protein concentrations are measured with a BSA assay. Through the use of immunoprecipitation-immunoblotting or capture ELISA, the amount of total and phosphorylated protein is measured.
References

[1]. An orally available small-molecule inhibitor of c-Met, PF-2341066, exhibits cytoreductive antitumor efficacy through antiproliferative and antiangiogenic mechanisms. Cancer Res. 2007, 67(9), 4408-4417.

[2]. Cytoreductive antitumor activity of PF-2341066, a novel inhibitor of anaplastic lymphoma kinase and c-Met, in experimental models of anaplastic large-cell lymphoma. Mol Cancer Ther. 2007, 6(12 Pt 1), 3314-3322.

[3]. Structure based drug design of crizotinib (PF-02341066), a potent and selective dual inhibitor of mesenchymal-epithelial transition factor (c-MET) kinase and anaplastic lymphoma kinase (ALK). J Med Chem. 2011 Sep 22;54(18):6342-63.

[4]. Differential (18)F-FDG and 3'-deoxy-3'-(18)F-fluorothymidine PET responses to pharmacologic inhibition of the c-MET receptor in preclinical tumor models. J Nucl Med. 2011 Aug;52(8):1261-7

[5]. c-Myc alterations confer therapeutic response and acquired resistance to c-Met inhibitors in MET-addicted cancers. Cancer Res. 2015 Nov 1;75(21):4548-59.

[6]. The kinase ALK stimulates the kinase ERK5 to promote the expression of the oncogene MYCN in neuroblastoma. Sci Signal. 2014 Oct 28;7(349):ra102.

[7]. Immunoassays for the quantification of ALK and phosphorylated ALK support the evaluation of on-target ALK inhibitors in neuroblastoma. Mol Oncol. 2017 Aug;11(8):996-1006.

[8]. Identifying and Targeting Sporadic Oncogenic GeneticLiu H, et al. Identifying and Targeting Sporadic Oncogenic Genetic Aberrations in Mouse Models of Triple Negative Breast Cancer. Cancer Discov. 2018 Mar;8(3):354-369.

These protocols are for reference only. InvivoChem does not independently validate these methods.
Physicochemical Properties
Molecular Formula
C21H22CL2FN5O
Molecular Weight
450.34
Exact Mass
449.12
Elemental Analysis
C, 56.01; H, 4.92; Cl, 15.74; F, 4.22; N, 15.55; O, 3.55
CAS #
877399-52-5
Appearance
white to off-white solid powder
SMILES
C[C@H](C1=C(C=CC(=C1Cl)F)Cl)OC2=C(N=CC(=C2)C3=CN(N=C3)C4CCNCC4)N
InChi Key
KTEIFNKAUNYNJU-GFCCVEGCSA-N
InChi Code
InChI=1S/C21H22Cl2FN5O/c1-12(19-16(22)2-3-17(24)20(19)23)30-18-8-13(9-27-21(18)25)14-10-28-29(11-14)15-4-6-26-7-5-15/h2-3,8-12,15,26H,4-7H2,1H3,(H2,25,27)/t12-/m1/s1
Chemical Name
3-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-(1-piperidin-4-ylpyrazol-4-yl)pyridin-2-amine
Synonyms
PF-2341066; PF2341066; PF02341066; PF-02341066; PF 2341066; Crizotinib; PF 02341066; US trade name: Xalkori
HS Tariff Code
2934.99.9001
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: ~9 mg/mL (~20 mM)
Water:<1 mg/mL
Ethanol: <1 mg/mL
Solubility (In Vivo)
5% DMSO+30% PEG 300+dd H2O: 5 mg/mL
 (Please use freshly prepared in vivo formulations for optimal results.)
Preparing Stock Solutions 1 mg 5 mg 10 mg
1 mM 2.2205 mL 11.1027 mL 22.2054 mL
5 mM 0.4441 mL 2.2205 mL 4.4411 mL
10 mM 0.2221 mL 1.1103 mL 2.2205 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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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
NCT02034981 Active
Recruiting
Drug: Crizotinib Hematologic Cancers
Solid Tumors
UNICANCER August 2013 Phase 2
NCT02223819 Active
Recruiting
Drug: Crizotinib Uveal Melanoma Columbia University March 2015 Phase 2
NCT04439266 Active
Recruiting
Drug: Crizotinib Advanced Lymphoma
Refractory Lymphoma
National Cancer Institute
(NCI)
August 12, 2015 Phase 2
NCT04439253 Active
Recruiting
Drug: Crizotinib Advanced Lymphoma
Refractory Lymphoma
National Cancer Institute
(NCI)
August 12, 2015 Phase 2
NCT01121588 Active
Recruiting
Drug: Crizotinib Neoplasms Malignant Pfizer March 22, 2011 Phase 1
Biological Data
  • Crizotinib (PF-02341066)

    Mol Cancer Ther. 2012 Jul;11(7):1557-64.

  • Crizotinib (PF-02341066)

    Mol Cancer Ther. 2012 Jul;11(7):1557-64.

  • Crizotinib (PF-02341066)
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