PF-2341066 (Crizotinib) is a potent, orally bioavailable, ATP-competitive small-molecule inhibitor of c-Met kinase and ALK (anaplastic lymphoma kinase) with IC50 values to be 4 and 25 nM for C-Met and ALK resepectively.PF-2341066 (Crizotinib) potently inhibited cell proliferation, which was associated with G1-S–phase cell cycle arrest and induction of apoptosis in ALK-positive ALCL cells (IC50 values=30 nM) but not ALK-negative lymphoma cells. The induction of apoptosis was confirmed using terminal deoxyribonucleotide transferase–mediated nick-end labeling and Annexin V staining (IC50 values=25–50 nM).
|Cell lines||Karpas299, SUDHL-1, or U-937 cells|
|Preparation method||Cell Proliferation/Survival Assays. Cells were seeded in 96-well plates at low density at 37°C in medium supplemented with 10% FBS (growth medium) and after 24 h were switched to low serum medium (2% FBS). Designated concentrations of PF-2341066 were added to each well and cells were incubated at 37°C for 72 h. A 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay (Promega) was done to determine the relative cell numbers. IC50 values were calculated by concentration-response curve fitting using a Microsoft Excel–based four-parameter analytic method.|
|Animal models||S.c. Xenograft Models in Athymic Mice|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
|Solubility||DMSO ≥23 mg/mL|
Brentuximab vedotin and crizotinib in anaplastic large-cell lymphoma.
Foyil KV, et al. Cancer J. 2012 Sep;18(5):450-6. PMID: 23006951.
Crizotinib for the Treatment of ALK-Rearranged Non-Small Cell Lung Cancer: A Success Story to Usher in the Second Decade of Molecular Targeted Therapy in Oncology.
Ou SH, et al. Oncologist. 2012 Sep 18. PMID: 22989574.
Activity and safety of crizotinib in patients with ALK-positive non-small-cell lung cancer: updated results from a phase 1 study.
Camidge DR, et al. Lancet Oncol. 2012 Oct;13(10):1011-9. PMID: 22954507.
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