Crizotinib hydrochloride |
| Catalog No.GC12616 |
El clorhidrato de crizotinib (PF-02341066 clorhidrato) es un inhibidor dual de ALK y c-Met biodisponible por vÍa oral, selectivo y competitivo con ATP con IC50 de 20 y 8 nM, respectivamente. El clorhidrato de crizotinib (clorhidrato de PF-02341066) inhibe la fosforilaciÓn de tirosina de NPM-ALK y la fosforilaciÓn de tirosina de c-Met con IC50 de 24 y 11 nM en ensayos basados en células, respectivamente. También es un inhibidor del protooncogén 1 de ROS (ROS1). El clorhidrato de crizotinib (PF-02341066 clorhidrato) tiene una inhibiciÓn eficaz del crecimiento tumoral.
Products are for research use only. Not for human use. We do not sell to patients.
Cas No.: 1415560-69-8
Sample solution is provided at 25 µL, 10mM.
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Crizotinib hydrochloride (PF-02341066 hydrochloride) is an orally bioavailable, selective, and ATP-competitive dual ALK and c-Met inhibitor with IC50s of 20 and 8 nM, respectively. Crizotinib hydrochloride (PF-02341066 hydrochloride) inhibits tyrosine phosphorylation of NPM-ALK and tyrosine phosphorylation of c-Met with IC50s of 24 and 11 nM in cell-based assays, respectively. It is also a ROS proto-oncogene 1 (ROS1) inhibitor. Crizotinib hydrochloride (PF-02341066 hydrochloride) has effective tumor growth inhibition[1][2][3].
PF-2341066 displays similar potency against c-Met phosphorylation in mIMCD3 mouse or MDCK canine epithelial cells with IC50 of 5 nM and 20 nM, respectivly. PF-2341066 shows improved or similar activity against NIH3T3 cells engineered to express c-Met ATP-binding site mutants V1092I or H1094R or the P-loop mutant M1250T with IC50 of 19 nM, 2 nM and 15 nM, respectively, compared with NIH3T3 cells expressing wild-type receptor with IC50 of 13 nM. In contrast, a marked shift in potency of PF-2341066 is observed against cells engineered to express c-Met activation loop mutants Y1230C and Y1235D with IC50 of 127 nM and 92 nM, respectively, compared with wild-type receptor. PF-2341066 also potently prevents the phosphorylation of c-Met in NCI-H69 and HOP92 cells, with IC50 of 13 nM and 16 nM, respectively, which express the endogenous c-Met variants R988C and T1010I, respectively[1].
PF-2341066 also potently inhibits NPM-ALK phosphorylation in Karpas299 or SU-DHL-1 ALCL cells with an IC50 of 24 nM. PF-2341066 potently prevents cell proliferation, which is associated with G(1)-S-phase cell cycle arrest and induction of apoptosis in ALK-positive ALCL cells with IC50 of 30 nM, but not ALK-negative lymphoma cells[2].
PF-2341066 reveals the ability to cause marked regression of large established tumors (> 600 mm3) in both the 50 mg/kg/day and 75 mg/kg/day treatment cohorts, with a 60% decrease in mean tumor volume over the 43-day administration schedule in the GTL-16 model. In an another study, PF-2341066 displays the ability to completely inhibits GTL-16 tumor growth for >3 months, with only 1 of 12 mice exhibiting a significant increase in tumor growth over the 3-month treatment schedule at 50 mg/kg/day. A significant dose-dependent reduction of CD31-positive endothelial cells is observed at 12.5 mg/kg/day, 25 mg/kg/day, and 50 mg/kg/day in GTL-16 tumors, indicating that inhibition of MVD shows a dose-dependent correlation to antitumor efficacy. PF-2341066 displays a significant dose-dependent reduction of human VEGFA and IL-8 plasma levels in both the GTL-16 and U87MG models. Marked inhibition of phosphorylated c-Met, Akt, Erk, PLCλ1, and STAT5 levels is observed in GTL-16 tumors following p.o. administration of PF-2341066[1].
Treatment of c-MET-amplified GTL-16 xenografts with 50 mg/kg PF-2341066 elicits tumor regression that is associated with a slow reduction in 18F-FDG uptake and decreases expression of the glucose transporter 1, GLUT-1[4].
Reference:
[1]. Zou HY, et al. 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]. Christensen JG, et al. 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]. Cui JJ, et al. 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]. Cullinane C, et al. 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
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Cell experiment: |
Tumor cells are seeded in 96-well plates at low density in media supplemented with 10% FBS (growth media) and transferred to serum-free media (0% FBS and 0.04% BSA) after 24 h. Appropriate controls or designated concentrations of PF-2341066 are added to each well, and cells are incubated for 24 to 72 h. Human umbilical vascular endothelial cells (HUVEC) are seeded in 96-well plates in EGM2 media for 5 to 6 h at > 20,000 cells per well and transferred to serum-free media overnight. The following day, appropriate controls or designated concentrations of PF-2341066 are added to each well, and after 1 h incubation, HGF is added to designated wells at 100 ng/mL. A 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay is done to determine the relative tumor cell or HUVEC numbers. |
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Animal experiment: |
Athymic mice bearing xenografts (300-800 mm3) are given PF-2341066 in water by oral gavage at designated dose levels. At designated times following PF-2341066 administration, mice are humanely euthanized, and tumors are resected. Tumors are snap frozen and pulverized using a liquid nitrogen-cooled cryomortar and pestle, protein lysates are generated, and protein concentrations are determined using a BSA assay. The level of total and phosphorylated protein is determined using a capture ELISA or immunoprecipitation-immunoblotting method. |
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References: [1]. Zou HY, et al. 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. |
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| Cas No. | 1415560-69-8 | SDF | |
| Chemical Name | (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine hydrochloride | ||
| Canonical SMILES | C[C@](OC(C=C(C(C=N1)=CN1C2CCNCC2)C=N3)=C3N)([H])C4=C(Cl)C=CC(F)=C4Cl.Cl | ||
| Formula | C21H23Cl3FN5O | M.Wt | 486.8 |
| Solubility | ≥ 100.4 mg/mL in DMSO, ≥ 101.4 mg/mL in EtOH, ≥ 52.2 mg/mL in Water | Storage | Store at -20°C |
| General tips | Please select the appropriate solvent to prepare the stock solution according to the
solubility of the product in different solvents; once the solution is prepared, please store it in
separate packages to avoid product failure caused by repeated freezing and thawing.Storage method
and period of the stock solution: When stored at -80°C, please use it within 6 months; when stored
at -20°C, please use it within 1 month. To increase solubility, heat the tube to 37°C and then oscillate in an ultrasonic bath for some time. |
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| Shipping Condition | Evaluation sample solution: shipped with blue ice. All other sizes available: with RT, or with Blue Ice upon request. | ||
| Prepare stock solution | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.0542 mL | 10.2712 mL | 20.5423 mL |
| 5 mM | 0.4108 mL | 2.0542 mL | 4.1085 mL |
| 10 mM | 0.2054 mL | 1.0271 mL | 2.0542 mL |
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Method for preparing in vivo formulation: Take μL DMSO master liquid, next add μL Corn oil, mix and clarify.
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Quality Control & SDS
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- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Average Rating: 5 (Based on Reviews and 24 reference(s) in Google Scholar.)
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