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).
|Source||Drug Des Devel Ther (2015). Figure 2. PF-2341066|
|Method||Matrigel invasion assay|
|Cell Lines||NPC cell|
|Incubation Time||48 h|
|Results||Distance of NPC cell scramble at 48 hours was 0.99±0.11 mm in plates of PF-2341066 alone, 0.67±0.07 mm in cisplatin alone, and 0.33±0.05 mm in combination, (P,0.05)|
|Source||Drug Des Devel Ther (2015). Figure 1. PF-2341066|
|Method||Cell proliferation assay|
|Cell Lines||HNE -1 cells|
|Incubation Time||48 h|
|Results||The half maximal inhibitory concentration of PF-2341066 alone is 0.79±0.21 μmol/L, while combination with cisplatin is 0.41±0.13 μmol/L. The inhibition rate increased by 23.4% and showed certain synergistic effects|
|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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Savolitinib (volitinib, AZD6094, HMPL-504) is a novel, potent, and selective MET inhibitor currently in clinical development in various indications, including PRCC. The IC50 values of this compound for c-Met and p-Met are 5 nM and 3 nM, respectively. It shows exquisite selectivity for c-Met over 274 kinase.
AMG 337 is an oral, small molecule, ATP-competitive, highly selective inhibitor of the MET receptor.
S49076 is a novel, potent inhibitor of MET, AXL/MER, and FGFR1/2/3 with IC50 values below 20 nmol/L.
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