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Crizotinib

產(chǎn)品活性：Crizotinib (PF-02341066) 是一種具有口服活性的，ATP 競(jìng)爭(zhēng)性的 ALK 和 c-Met 抑制劑，IC₅₀ 分別為 20 和 8 nM。在細(xì)胞的實(shí)驗(yàn)中，Crizotinib 抑制 NPM-ALK 的酪氨酸磷酸化和 c-Met 的酪氨酸磷酸化，IC₅₀ 分別為 24 和 11 nM。Crizotinib 也是 ROS1 抑制劑。Crizotinib 具有有效的腫瘤生長(zhǎng)抑制作用。

研究領(lǐng)域：Protein Tyrosine Kinase/RTK  |  Autophagy

作用靶點(diǎn)：Anaplastic lymphoma kinase (ALK)  |  c-Met/HGFR  |  ROS Kinase  |  Autophagy

In Vitro: Crizotinib (PF-02341066) 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.
Crizotinib (PF-02341066) 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.

In Vivo: Crizotinib (PF-02341066) 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.
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.

相關(guān)產(chǎn)品：Drug Repurposing Compound Library Plus  |  FDA-Approved Drug Library Plus  |  FDA-Approved Drug Library Mini  |  Bioactive Compound Library Plus  |  Kinase Inhibitor Library  |  Protein Tyrosine Kinase Compound Library  |  FDA-Approved Drug Library  |  Anti-Cancer Compound Library  |  Autophagy Compound Library  |  Drug Repurposing Compound Library  |  NMPA-Approved Drug Library  |  Orally Active Compound Library  |  Glutamine Metabolism Compound Library  |  FDA Approved & Pharmacopeial Drug Library  |  Anti-Lung Cancer Compound Library  |  Drug-Induced Liver Injury (DILI) Compound Library  |  Anti-Pancreatic Cancer Compound Library  |  Anti-Blood Cancer Compound Library  |  Targeted Therapy Drug Library   |  Angiogenesis-Related Compound Library  |  Anti-Liver Cancer Compound Library   |  Rare Diseases Drug Library  |  Anti-Colorectal Cancer Compound Library   |  EMA-Approved Drug Library  |  FDA-Approved Anticancer Drug Library  |  Anti-Prostate Cancer Compound Library  |  Non-steroidal Anti-Inflammatory Compound Library  |  Cancer Stem Cells Compound Library  |  Heterocyclic Compound Library  |  Mitochondrial Protection Compound Library  |  Membrane Protein-targeted Compound Library  |  Membrane Receptor-targeted Compound Library  |  AMG-208  |  DS-1205b free base  |  ALK/ROS1-IN-1  |  MitoPQ  |  c-Met-IN-1  |  Ceritinib  |  Glumetinib  |  KRCA-0008  |  GGTI-2418  |  Savolitinib  |  Iruplinalkib  |  Antitumor agent-60  |  c-Met-IN-11  |  ABN401  |  Foretinib  |  ALK-IN-22  |  Taletrectinib free base  |  Anticancer agent 59  |  JH-VIII-157-02  |  Bafisontamab  |  MK-2461  |  Dalmelitinib  |  MK-8033 hydrochloride  |  NVP-TAE 684  |  AChE/BChE/BACE-1-IN-2  |  c-Met-IN-12  |  MET kinase-IN-4  |  Antitumor agent-55  |  ROS kinases-IN-2  |  Cabozantinib

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