生物活性

• 靶点

  ALK IC50:24nM

  c-Met IC50:11nM

• 描述c-Met, the prototypic member of a subfamily of RTKs, and its ligand HGF, are implicated in the progression of several human cancers and are attractive therapeutic targets. Activation of c-Met results in the binding and phosphorylation of adaptor proteins, such as Gab1, Grb2, Shc and c-Cbl and subsequent activation of signal transducers such as PI3K, Akt, PLC-γ, STAT and ERK1/2. Crizotinib is a potent and selective inhibitor of c-Met with Ki value of 4nM (measured by c-Met kinase activity) and ALK with IC50 value of 24nM (based on cell study). Antitumor activity of Crizotinib may be mediated by both direct effects on tumor cell growth or survival, as well as antiangiogenic mechanisms. It inhibited growth and induced apoptosis of human GTL-16 gastric carcinoma with IC50s of 9.7nM and 8.4nM, respectively, blocked the cell migration and invasion induced by HGF in NCI-H441 lung carcinoma cells with IC50 of 11nM and 6.1nM, as well as inhibited MDCK cell scattering with IC50 of 16nM. Treatment with Crizotinib resulted in inhibition on serum-stimulated HMVEC branching tubulogenesis, as well as inhibition on HGF-stimulated c-Met phosphorylation, cell survival and Matrigel invasion with IC50 values of 11nM, 14nM and 35nM, respectively, in HUVEC cells. And this two mechanism of anti-tumor effect also acted in tumor models. Oral administration of Crizotinib at dose of 6.25mg/kg, 12.5mg/kg and 50mg/kg showed tumor growth inhibition on 30%, 60% and 100% in c-Met–dependent GTL-16 tumor xenograft model with dose-dependent decrease in c-Met phosphorylation. The effect of Crizotinib on signal transduction pathways can be observed in tumors in vivo, as levels of phosphorylated c-Met, Akt, Erk, PLCE1 and STAT5 decreased in athymic mice bearing established GTL-16 xenografts orally administrated with Crizotinib at dose of 25 or 50mg/kg for 11 days^[1].
• 作用机制Crizotinib preferentially binds to the ATP binding pocket of ALK in its inactive conformation.^[1]
• 细胞研究
• Cell Data

  Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
  3T3	-	Function Assay	1 h	Inhibition of RON assessed as growth factor-induced autophosphorylation with IC50 of 0.08 μM	21812414
  3T3-E	-	Function Assay	1 h	Inhibition of TIE2 assessed growth factor-induced autophosphorylation with IC50 of 0.448 μM	21812414
  697	-	Growth Inhibition Assay	-	IC50=9.24329 μM	SANGER

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• 动物研究
  剂量	Nude Mice: 12.5 mg/kg - 50 mg/kg[4] (p.o.), 25 mg/kg - 200 mg/kg[5] (p.o.)
  给药途径	p.o.
  动物药代数据	Animal Rats[5] Dogs[5] Dose 50 mg/kg (p.o.) 5 mg/kg (i.v.) 10 mg/kg (p.o.) 5 mg/kg (i.v.) Administration p.o. i.v. p.o. i.v. F 60 ± 19 (%) (p.o.) 52 ± 44 (%) (p.o.) T1/2 6.6 ± 2.6 h (p.o.) 9.6 ± 1.0 h (i.v.) 13 ± 2 h (p.o.) 17 ± 4 h (i.v.) Tmax 5.3 ± 1.2 h (p.o.) 3 ± 3 h (p.o.) CL 47 ± 6 ml/min/kg (i.v.) 9.0 ± 0.7 ml/min/kg (i.v.) Cmax 780 ± 200 ng/ml (p.o.) 620 ± 510 ng/ml (p.o.) AUC0→∞ 11,000 ± 300 ng·h/ml (p.o.) 1800 ± 200 ng·h/ml (i.v.) 9700 ± 6800 ng·h/ml (p.o.) 5900 ± 300 ng·h/ml (i.v.) Vss 24 ± 4 L/kg (i.v.) 13 ± 2 L/kg (i.v.)

• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT02559778	Neuroblastoma	Phase 2	Recruiting	September 2026	-
  NCT03737994	ALK Gene Rearrangement ... more >> ALK Positive Non-Squamous Non-Small Cell Lung Carcinoma Stage IV Lung Cancer AJCC v8 Stage IVA Lung Cancer AJCC v8 Stage IVB Lung Cancer AJCC v8 Collapse <<	Phase 2	Not yet recruiting	December 13, 2025	-
  NCT01871805	Non-Small Cell Lung Cancer	Phase 1 Phase 2	Completed	-	-

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• 参考文献

• [1] Zou HY, Li Q, 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):4408-17.

  [2] Yamazaki S, Vicini P, et al. Pharmacokinetic/pharmacodynamic modeling of crizotinib for anaplastic lymphoma kinase inhibition and antitumor efficacy in human tumor xenograft mouse models. J Pharmacol Exp Ther. 2012;340(3):549-57

  [3] Zhou WJ, Zhang X, et al. Crizotinib (PF-02341066) reverses multidrug resistance in cancer cells by inhibiting the function of P-glycoprotein. Br J Pharmacol. 2012;166(5):1669-83.

  [4] Baschnagel AM, Galoforo S, et al. Crizotinib Fails to Enhance the Effect of Radiation in Head and Neck Squamous Cell Carcinoma Xenografts. Anticancer Res. 2015 Nov;35(11):5973-82.

  [5] Crizotinib

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