Crizotinib (PF-02341066)

Crizotinib (PF-02341066) は1種の有効な小分子の卵白の阻害剤の再編人プロテインキナーゼ、 Kiが 4 nM。

目録号S1068
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Crizotinib (PF-02341066) 化学構造
分子量: 450.34

品質と確認

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Quality Control & MSDS

製品情報

  • Combination Therapy
    併用療法
  • Compare c-Met Inhibitors
    c-Met阻害剤を比較
  • 研究分野
  • Crizotinib (PF-02341066)のメカニズム

製品の説明

生物活性

情報 Crizotinib (PF-02341066) は1種の有効な小分子の卵白の阻害剤の再編人プロテインキナーゼ、 Kiが 4 nM。
目標 c-Met ALK
IC50 11 nM 24 nM [1]
In vitro試験 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. PF-2341066 is >1,000-fold selective for the VEGFR2 and PDGFRβ RTKs, >250-fold selective for IRK and Lck, and ∼40- to 60-fold selective for Tie2, TrkA, and TrkB, all compared with c-Met. PF-2341066 is 20- to 30-fold selective for RON and Axl RTKs. In contrast, PF-2341066 shows a near-equivalent IC50 of 24 nM against the nucleophosmin (NPM)-anaplastic lymphoma kinase (ALK) oncogenic fusion variant of the ALK RTK expressed by the KARPAS299 human anaplastic large cell lymphoma (ALCL) cell line. PF-2341066 inhibits c-Met–dependent neoplastic phenotypes of cancer cells and angiogenic phenotypes of endothelial cells. PF-2341066 suppresses human GTL-16 gastric carcinoma cell growth with IC50 of 9.7 nM. PF-2341066 induces apoptosis in GTL-16 cells with IC50 of 8.4 nM. PF-2341066 inhibits HGF-stimulated human NCI-H441 lung carcinoma cell migration and invasion with IC50 of 11 nM and 6.1 nM, respectively. PF-2341066 inhibits MDCK cell scattering with IC50 of 16 nM. PF-2341066 prevents HGF-stimulated c-Met phosphorylation, cell survival, and Matrigel invasion with IC50 of 11 nM, 14 nM and 35 nM, respectively. In addition, PF-2341066 prevents serum-stimulated HMVEC branching tubulogenesis (formation of vascular tubes) in fibrin gels. [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] Besides, PF-2341066 prevents osteosarcoma behavior associated with primary tumor growth (i.e., proliferation and survival) as well as metastasis (eg, invasion and clonogenicity). [3]
In vivo試験 In the GTL-16 model, 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 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. In the NCI-H441 NSCLC model, a 43% decrease in mean tumor volume is observed at 50 mg/kg/day during the 38-day PF-2341066 administration cycle. In the Caki-1 RCC model, a 53% decrease in mean tumor volume is observed to be associated with decreased volume of each tumor by at least 30% at 50 mg/kg/day during the 33-day PF-2341066 administration cycle. PF-2341066 also reveals near-complete prevention of the growth of established tumors at 50 mg/kg/day in the U87MG glioblastoma or PC-3 prostate carcinoma xenograft models, with 97% or 84% inhibition on the final study day, respectively. In contrast, PF-2341066 p.o. given at 50 mg/kg/day does not significantly inhibit tumor growth in the MDA-MB-231 breast carcinoma model, or the DLD-1 colon carcinoma model. 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] P.o. administration of PF-2341066 to severe combined immunodeficient-Beige mice bearing Karpas299 ALCL tumor xenografts leads to dose-dependent antitumor efficacy with complete regression of all tumors at the 100 mg/kg/d dose within 15 days of initial compound administration. In addition, inhibition of key NPM-ALK signaling mediators, including phospholipase C-gamma, signal transducers and activators of transcription 3, extracellular signal-regulated kinases, and Akt by PF-2341066 are observed at concentrations or dose levels, which correlated with inhibition of NPM-ALK phosphorylation and function.[2] PF-2341066 prevents osteosarcoma behavior associated with primary tumor growth (eg, proliferation and survival) as well as metastasis (eg, invasion and clonogenicity). In nude mice treated with PF-2341066 via oral gavage, the growth and associated osteolysis and extracortical bone matrix formation of osteosarcoma xenografts are prevented by PF-2341066.[3] 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]
臨床試験 PF-2341066 is currently in a Phase III clinical trial in the treatment of non squamous lung cancer.
特集

推薦された実験操作 (公開の文献だけ)

キナーゼアッセイ: [1]

Cellular kinase phosphorylation ELISA assays Cells are seeded in 96-well plates in media supplemented with 10% fetal bovine serum (FBS) and transferred to serum-free media [with 0.04% bovine serum albumin (BSA)] after 24 h. In experiments investigating ligand-dependent RTK phosphorylation, corresponding growth factors are added for up to 20 min. After incubation of cells with PF-2341066 for 1 h and/or appropriate ligands for the designated times, cells are washed once with HBSS supplemented with 1 mM Na3VO4, and protein lysates are generated from cells. Subsequently, phosphorylation of selected protein kinases is assessed by a sandwich ELISA method using specific capture antibodies used to coat 96-well plates and a detection antibody specific for phosphorylated tyrosine residues. Antibody-coated plates are (a) incubated in the presence of protein lysates at 4°C overnight; (b) washed seven times in 1% Tween 20 in PBS; (c) incubated in a horseradish peroxidase–conjugated anti–total-phosphotyrosine (PY-20) antibody (1:500) for 30 min; (d) washed seven times again; (e) incubated in 3,3′,5,5′-tetramethyl benzidine peroxidase substrate to initiate a colorimetric reaction that is stopped by adding 0.09 N H2SO4; and (f) measured for absorbance in 450 nm using a spectrophotometer.

細胞アッセイ: [1]

細胞系 GTL-16 gastric carcinoma cells and T47D breast carcinoma cells
濃度 0-256 nM
処理時間 1 hour
方法 Cells including GTL-16 gastric carcinoma cells and T47D breast carcinoma cells are seeded in 96-well plates in media supplemented with 10% fetal bovine serum (FBS) and transferred to serum-free media [with 0.04% bovine serum albumin (BSA)] after 24 hours. In experiments investigating ligand-dependent RTK phosphorylation, corresponding growth factors are added for up to 20 minutes. After incubation of cells with PF-2341066 for 1 hour and/or appropriate ligands for the designated times, cells are washed once with HBSS supplemented with 1 mM Na3VO4, and protein lysates are generated from cells. Subsequently, phosphorylation of selected protein kinases is assessed by a sandwich ELISA method using specific capture antibodies used to coat 96-well plates and a detection antibody specific for phosphorylated tyrosine residues. Antibody-coated plates are (a) incubated in the presence of protein lysates at 4 °C overnight; (b) washed seven times in 1% Tween 20 in PBS; (c) incubated in a horseradish peroxidase–conjugated anti–total-phosphotyrosine (PY-20) antibody (1:500) for 30 min; (d) washed seven times again; (e) incubated in 3,3,5,5-tetramethyl benzidine peroxidase substrate to initiate a colorimetric reaction that is stopped by adding 0.09 N H2SO4; and (f) measured for absorbance in 450 nm using a spectrophotometer.

動物実験: [1]

動物モデル Female or male nu/nu mice bearing NCI-H441,or DLD-1, or MDA-MB-231
製剤
投薬量 12.5 mg/kg/day, 25 mg/kg/day, and 50 mg/kg/day
管理 Administered via p.o.
1

参考

化学情報

Download Crizotinib (PF-02341066) SDF
分子量 450.34
化学式

C21H22Cl2FN5O

CAS No. 877399-52-5
別名 N/A
溶解度 (25°C)
  • DMSO 9 mg/mL
  • 水 <1 mg/mL
  • エタノール <1 mg/mL
保管 2年 -20°C
6月-80°Cin DMSO
化学名 3-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine

研究分野

カスタマーレビュー (8)


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Rating
Source Cancer Cell , 2011, 19, 679–690. Crizotinib (PF-02341066) purchased from Selleck
Method Immunoblot analysis, Tumor growth inhibition Assay
Cell Lines xenograft models
Concentrations 100 mg/kg
Incubation Time 8 days
Results We showed that administration of CH5424802 led to significant tumor regression against both native EML4-ALK- and L1196M-driven tumors. On the other hand, PF-02341066 (100 mg/kg) resulted in no significant tumor growth inhibition against L1196M-driven tumors. Furthermore, we confirmed that phospho-STAT3, one of the downstream targets of ALK, was abolished in both tumors that were treated with CH5424802.

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Source Nat Med , 2011, 17, 1116-1120. Crizotinib (PF-02341066) purchased from Selleck
Method Western blot
Cell Lines RCT-E565 transplanted tumors
Concentrations 25 mg/kg/d, 50 mg/kg/d
Incubation Time 0-21 d
Results We then treated mice bearing RCT-E565 tumor transplants with PF02341066, a c-Met inhibitor currently in clinical development. PF02341066 abrogated both p-Akt and p-S6RP signals as well as tumor growth.

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Rating
Source Int J Proteomics , 2011, 2011, Article ID 215496. Crizotinib (PF-02341066) purchased from Selleck
Method CEER assay
Cell Lines H1993 cell line
Concentrations 0-10 μM
Incubation Time 4 h
Results In the c-MET amplified cell line H1993, activation of this pathway was blocked by the treatment with PF-2341066, a c-MET kinase inhibitor.

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Rating
Source Int J Proteomics , 2011, 2011, Article ID 215496. Crizotinib (PF-02341066) purchased from Selleck
Method Nikon inverted-phase microscope
Cell Lines lung tumor cell lines
Concentrations 0.1/1 µM
Incubation Time two weeks
Results Large colony formation of H1993 cells, whose proliferation in tissue culture was potently blocked by treatment with the c-MET kinase inhibitor PF-2341066, was also inhibited by treatment with the same inhibitor.

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Rating
Source Dr. Zhang of Tianjin Medical University. Crizotinib (PF-02341066) purchased from Selleck
Method Western blot
Cell Lines MDA-MB-231 cell line
Concentrations 0-100 nM
Incubation Time
Results

Click to enlarge
Rating
Source Cancer Cell , 2011, 19, 679–690. Crizotinib (PF-02341066) purchased from Selleck
Method Cell Growth Inhibition Assay
Cell Lines Ba/F3 cells
Concentrations
Incubation Time 48 h
Results The sensitivities of L1196M-driven Ba/F3 cell clones to PF-02341066 were lower, closely resembling that of the Ba/F3 parental cells. The therapeutic indexes of CH5424802 and PF-02341066, the IC50 ratio of EML4-ALK L1196M-driven cell clones to the parental cells, were 7- to 12-fold and 1- to 2-fold.

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Rating
Source J Biomol Screen , 2011, 16, 141-154. Crizotinib (PF-02341066) purchased from Selleck
Method VimPro-Fluc-MDA-MB-231 spheroid viability, Western blot
Cell Lines MDA-MB-231 spheroids
Concentrations
Incubation Time
Results When Vimpro-Fluc downregulation reaches ≥70%, then downregulation of vimentin protein expression is more pronounced. of the modulators tested—U0126, dasatinib,axitinib, and pF2341066-all downregulated Vimpro-Fluc activity by ≥70%, which correlated with a significant down-reglation of vimentin protein expression. Finally, dose-response curves were generated with both U0126 (iC50 = 2.5 µM) and axitinib (iC50 = 0.25 µM), demonstrating that these small molecules modulate Vimpro-Fluc activity in a dose-dependent manner, indicating that their respective target(s) and signaling pathways play a significant role in maintaining vimentin expression and possibly mesenchymal homeostasis (Fig. B)

Click to enlarge
Rating
Source J Biomol Screen , 2011, 16, 141-154. Crizotinib (PF-02341066) purchased from Selleck
Method Secondary assay
Cell Lines MDA-MB-231 spheroids
Concentrations 10 µM
Incubation Time
Results U0126, pF2341066, axitinib, and pKC412 caused significant inhibition of the invasive potential of Mda-Mb-231 spheroids. Conversely, dasatinib, a potent inhibitor of vimentin gene expression, did not significantly alter the invasive potential of Mda-Mb-231 spheroids.

製品表彰状 (31)

  • Widespread potential for growth-factor-driven resistance to anticancer kinase inhibitors. [Wilson TR, et al. Nature 2012;487(7408):505-9]

    PubMed: 22763448
  • MED12 controls the response to multiple cancer drugs through regulation of TGF-β receptor signaling. [Huang S, et al. Cell 2012;151(5):937-50]

    PubMed: 23178117
  • CH5424802, a selective ALK inhibitor capable of blocking the resistant gatekeeper mutant. [Sakamoto H, et al. Cancer Cell 2011;19(5):679-90]

    PubMed: 21575866
  • Oncogenic PIK3CA-driven mammary tumors frequently recur via PI3K pathway–dependent and PI3K pathway–independent mechanisms. [Liu P, et al. Nat Med 2011;17(9):1116-20]

    PubMed: 21822287
  • Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET. [Peinado H, et al. Nat Med 2012;18(6):883-91]

    PubMed: 22635005
  • A drug resistance screen using a selective MET inhibitor reveals a spectrum of mutations that partially overlap with activating mutations found in cancer patients. [Tiedt R, et al. Cancer Res 2011;71(15):5255-64]

    PubMed: 21697284
  • ALK+ anaplastic large cell lymphoma exhibits phosphatidylinositol-3 kinase/Akt activity with retained but inactivated PTEN--a report from the Children's Oncology Group. [Heuckmann JM, et al. Clin Cancer Res 2011;59(3):440-7]

    PubMed: 21948233
  • Characteristics of lung cancers harboring NRAS mutations. [Ohashi K, et al. Clin Cancer Res 2013;19(9):2584-91]

    PubMed: 23515407
  • Epithelial-mesenchymal transition leads to crizotinib resistance in H2228 lung cancer cells with EML4-ALK translocation. [Hyeong Ryul Kim, et al. MOLECULAR ONCOLOGY 2013;7(6):1093-102]

    PubMed: 23993685
  • Expression and clinical relevance of MET and ALK in Ewing sarcomas. [Fleuren ED, et al. Int J Cancer 2013;133(2):427-36]

    PubMed: 23335077
  • Overcoming erlotinib resistance with tailored treatment regimen in patient-derived xenografts from naïve Asian NSCLC patients. [Yang M, et al. Int J Cancer 2013;132(2):E74-84]

    PubMed: 22948846
  • Identification of basophils as a major source of hepatocyte growth factor in chronic myeloid leukemia: a novel mechanism of BCR-ABL1-independent disease progression. [Cerny-Reiterer S, et al. Neoplasia 2012;14(7):572-84]

    PubMed: 22904675
  • Colloidal Aggregation Affects the Efficacy of Anticancer Drugs in Cell Culture. [Owen SC, et al. ACS Chem Biol 2012;7(8):1429-35]

    PubMed: 22625864
  • High ALK mRNA expression has a negative prognostic significance in rhabdomyosarcoma. [Bonvini P, et al. Br J Cancer 2013;109(12):3084-91]

    PubMed: 24149177
  • Crizotinib (PF‐02341066) Reverses Multidrug Resistance in Cancer Cells by Inhibiting the function of P‐glycoprotein. [Zhou WJ, et al. Br J Pharmacol 2012;166(5):1669-83]

    PubMed: 22233293
  • Disturbance of Ca2+ homeostasis converts Pro-Met into non-canonical tyrosine kinase p190MetNC in response to endoplasmic reticulum stress in MHCC97 cells. [Dai R, et al. J Biol Chem 2012;287(18):14586-97]

    PubMed: 22418436
  • The Tyrosine Kinase c-Met Contributes to the Pro-tumorigenic Function of the p38 Kinase in Human Bile Duct Cholangiocarcinoma Cells. [Dai R, et al. J Biol Chem 2012;287(47):39812-23]

    PubMed: 23024367
  • A Receptor Tyrosine Kinase Network Comprised of FGFRs, EGFR, ERBB2 and MET Drives Growth and Survival of Head and Neck Squamous Carcinoma Cell Lines. [Singleton KR, et al. Mol Pharmacol 2013;83(4):882-93]

    PubMed: 23371912
  • Mouse Model for ROS1-Rearranged Lung Cancer. [Arai Y, et al. PLoS One 2013;8(2):e56010]

    PubMed: 23418494
  • STAT3 is activated by JAK2 independent of key oncogenic driver mutations in non-small cell lung carcinoma. [Looyenga BD, et al. PLoS One 2012;7(2):e30820]

    PubMed: 22319590
  • Heregulin induces resistance to lapatinib-mediated growth inhibition of HER5-amplified cancer cells. [Sato Y, et al. Cancer Sci 2013;104(12):1618-25]

    PubMed: 24112719
  • Activating mutations in ALK kinase domain confer resistance to structurally unrelated ALK inhibitors in NPM-ALK-positive anaplastic large-cell lymphoma [Zdzalik D J Cancer Res Clin Oncol 2014;10.​1007/​s00432-014-1589-3]

    PubMed: 24509625
  • Phosphoproteomic analysis identifies activated MET-axis PI3K/AKT and MAPK/ERK in lapatinib-resistant cancer cell line. [Lee YY, et al. Exp Mol Med 2013;45:e64]

    PubMed: 24263233
  • ALK mutations conferring differential resistance to structurally diverse ALK inhibitors. [Thakral C, et al. Pediatr Blood Cancer 2012;17(23):7394-401]

    PubMed: 22488797
  • 3D models of epithelial-mesenchymal transition in breast cancer metastasis: high-throughput screening assay development, validation, and pilot screen. [Li Q, et al. J Biomol Screen 2011;16(2):141-54]

    PubMed: 21297102
  • Colloidal Drug Formulations Can Explain "Bell-Shaped" Concentration-Response Curves. [Owen SC ,et al. ACS Chem Biol 2013;10.1021/cb4007584]

    PubMed: 24397822
  • Unacylated Ghrelin Promotes Skeletal Muscle Regeneration Following Hindlimb Ischemia via SOD-2-Mediated miR-221/222 Expression. [Togliatto G, et al. J Am Heart Assoc 2013;2(6):e000376]

    PubMed: 24308935
  • The growth inhibitory effect of 17-DMAG on ALK and MYCN double-positive neuroblastoma cell line. [Yi B, et al. Tumour Biol 2013;10.1007/s13277-013-1422-7]

    PubMed: 24293393
  • Signatures of drug sensitivity in nonsmall cell lung cancer. [Gong HC, et al. Int J Proteomics 2011;2011:215496]

    PubMed: 22091388
  • Presence of anaplastic lymphoma kinase in inflammatory breast cancer. [Robertson FM, et al. Springerplus 2013;2:497]

    PubMed: 24102046
  • Epithelial-mesenchymal transition confers resistance to FGFR inhibitors in gastric cancer cell line [Paulina Grygielewicz, et al. CELON PHARMA 2013;2013]

技術サポート&よくある質問(FAQ)

顧客がするかもしれない質問に対する答えは、指示を取り扱っている阻害剤で見つかります。話題は、貯蔵液(阻害剤と特別な注意を細胞ベースの分析法と動物のために必要とする問題を保存することは実験します)を準備する方法を含みます。

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