Dasatinib 化学構造
分子量: 488.01

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カスタマーレビュー(10)

Quality Control & MSDS

製品情報

  • Combination Therapy
    併用療法
  • Compare Src Inhibitors
    Src阻害剤を比較
  • 研究分野

製品の説明

生物活性

情報 Dasatinib は、野生型ablとSrcのためのSrc/abl阻害剤で、IC50 がそれぞれ 0.6 nM と 0.8 nMです。
目標 Abl Src c-Kit (WT)/c-Kit (D816V)
IC50

0.6 nM

0.8 nM [1]

79 nM/37 nM [2]
In vitro試験 Dasatinib is more effective than imatinib in inhibiting the proliferation of Ba/F3 cells expressing wild-type Bcr-Abl and Bcr-Abl mutants, with the exception of T315I. Dasatinib has a two-log (∼325-fold) increased potency relative to imatinib. Dasatinib potently inhibits wild-type Abl kinase and all mutants except T315I over a narrow range. Dasatinib directly targets wild-type and mutant Abl kinase domains and inhibits autophosphorylation and substrate phosphorylation in a concentration-dependent manner. Dasatinib displays 325-fold greater potency compared with imatinib against cells expressing wild-type Bcr-Abl. [1] The percent of colonies of TgE bone marrow cells are decreased from 100% in untreated wells to 4.12% in Dasatinib treated wells. In the presence of Dasatinib, the difference in the percentage of colonies formed by WT and TgE bone marrow cells is statistically significant. Expression of LMP2A is able to promote B lymphocyte survival and proliferation, which can be inhibited by targeting Lyn and/or c-Abl kinases through Dasatinib. [3] Dasatinib treatment inhibits Src signaling, decreases growth, and induces cell cycle arrest and apoptosis in a subset of thyroid cancer cells. Treatment with increasing doses of Dasatinib (0.019 μM to 1.25 μM) for 3 days inhibits the growth of the C643, TPC1, BCPAP, and SW1736 cell lines by about 50% at low nanomolar concentrations, while higher concentrations are required to inhibit the growth of the K1 cell line. Treatment with 10 nM or 50 nM Dasatinib results in a 9-22% increase of cells in the G1 population among BCPAP and SW1736 and K1 cells, and a corresponding 7-18% decrease in the percentage of cells in the S phase. [4]
In vivo試験 Dasatinib reverses splenomegaly in LMP2A/MYC double transgenic mice. Dasatinib specifically prevents colony formation by LMP2A expressing bone marrow B cells and decreased spleen size in the TgE mice. Spleen mass is significantly decreased among Dasatinib treated Tg6/λ-MYC mice when compared to the control group. Dasatinib inhibits lymphadenopathy in LMP2A/MYC double transgenic mice. Dasatinib reverses splenomegaly in Rag1KO mice engrafted with tumor cells from LMP2A/MYC double transgenic mice. Dasatinib therapy inhibits Lyn phosphorylation in B lymphocyte tumors expressing LMP2A. [3]
臨床試験 Dasatinib has entered in a phase II clinical trial in the treatment of hemangiopericytoma and gastrointestinal stromal tumor.
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]

Kinase autophosphorylation assays Kinase assays using wild-type and mutant glutathione S-transferase (GST)-Abl fusion proteins (c-Abl amino acids 220-498) are done. GST-Abl fusion proteins are released from glutathione-Sepharose beads before use; the concentration of ATP is 5 μM. Immediately before use in kinase autophosphorylation and in vitro peptide substrate phosphorylation assays, GST-Abl kinase domain fusion proteins are treated with LAR tyrosine phosphatase. After 1-hour incubation at 30 °C, LAR phosphatase is inactivated by addition of sodium vanadate (1 mM). Immunoblot analysis comparing untreated GST-Abl kinase to dephosphorylated GST-Abl kinase is routinely done using phosphotyrosine-specific antibody 4G10 to confirm complete (>95%) dephosphorylation of tyrosine residues and c-Abl antibody CST 2862 to confirm equal loading of GST-Abl kinase. The Dasatinib concentration range is extended to 1,000 nM for mutant T315I. These same inhibitor concentrations are used for the in vitro peptide substrate phosphorylation assays. The three inhibitors are tested over these same concentration ranges against GST-Src kinase and GST-Lyn kinase.

細胞アッセイ:

[1]

細胞系 Ba/F3 cell lines
濃度 ~32 nM
処理時間 72 hours
方法

Ba/F3 cell lines are seeded in triplicate and incubated with escalating concentrations of Dasatinib for 72 hours. Proliferation is measured using a methanethiosulfonate-based viability assay. IC50 and IC90 values are reported as the mean of three independent experiments done in quadruplicate. The inhibitor concentration ranges are 0 nM to 32 nM (Dasatinib). The Dasatinib concentration range is extended to 200 nM for mutant T315I.

動物実験:

[3]

動物モデル EμLMP2A (TgE and Tg6 strains), MYC (λ-MYC), and LMP2A/λ-MYC double transgenic mice (Tg6/λ-MYC)
製剤 DMSO
投薬量 30 mg/kg
管理 Administered via i.p.
1

参考

化学情報

Download Dasatinib SDF
分子量 488.01
化学式

C22H26ClN7O2S

CAS No. 302962-49-8
別名 Sprycel
溶解度 (25°C)
  • DMSO 98 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 N-(2-chloro-6-methylphenyl)-2-(6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide

研究分野

カスタマーレビュー (10)


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Source Invest New Drugs , 2010, 30(1), 417-422. Dasatinib purchased from Selleck
Method Western blot
Cell Lines p53wild-type(EHEB, JVM-2) cell lines, p53mutated(MEC-2, BJAB) cell lines
Concentrations 10 μM
Incubation Time 24 h
Results "Upon exposure to Dasatinib, a decrease of phosphorylated proteins was confirmed by Western blot analys is in all cell lines investigated without significant differences between p53wild-type and p53mutated cell lines.

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Source Biochem Pharmacol , 2011, 82(10), 1457-1466. Dasatinib purchased from Selleck
Method Evaluation of differentiation
Cell Lines MOLM-13 cells, HL-60 cells
Concentrations 5 μM
Incubation Time
Results In a first series of experiments, we assessed four signs of morphological differentiation, May-Gruenwald-Giemsa staining of MOLM-13 cells demonstrated that dasatinib induced a dose-dependent decrease in cytoplasmic basophilia and in the nucleo-cytoplasmic ratio. Dasatinib also led to the appearance of dented nuclei and cytoplasmic granulation( Fig.A and B).In HL-60 cells,dasatinib(5 μM) once more exhibited the highest differentiation-inducing capacity. Thus dasatinib diminished basophilia of the cytoplasm concomitantly with the nucleo-cytoplasmic ratio, and induced the appearance of nuclear lobulation and cytoplasmic granules(Fig. G). Next, we determined the degree of CD11b expression, a marker indicating myeloid differentiation, in TKI-treated MOLM-13 dasatinib exhibited the most pronounced capacity to increase CD11b surface expression( Fig. C and D).To corroborate the TKI-driven differentiation, we quantified the enzymatic activity of alkaline phosphatase by means of the NBT-reduction assay after an incubation period of 6 days in MOLM-13 cells.,Once again, the NBT-reductive activity was highest in cells treated with dasatinib, which was as active as the positive control, ATRA( Fig. E and F)

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Rating
Source Invest New Drugs , 2010, 30(1), 417-422. Dasatinib purchased from Selleck
Method Assessment of cell viability
Cell Lines leukemic cells
Concentrations 10 μM
Incubation Time 24/48 h
Results Dasatinib dose-dependently reduced cell viability in all leukemic cell lines, with variable efficacy irrespect ively of the p53 status. In particular, when used at 10 μM, Dasatinib induced a progressive decrease of the total number of viable cells ranging from approximately 30% (JVM-2 and MEC-2) to 50% (EHEB and BJAB) after 48 h of treat ment (Fig.a). In order to investigate whet her the decreased leukemic cell viability was mainly due to either cytotoxic or cytostatic activity, we have analyzed the effects of Dasatinib on apoptosis,As shown in Fig. b, exposure to Dasatinib induced a significant (p < 0.05) increase of apoptosis in all leukemic cell lines, as evaluated by Annexin-V/PI staining at 48 h of treatment.

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Rating
Source Invest New Drugs , 2010, 30(1), 417-422. Dasatinib purchased from Selleck
Method phospho-kinase array analysis
Cell Lines EHEB (p53wt) cell lines, BJAB (p53mut) B cell lines
Concentrations
Incubation Time 24 h
Results As shown in Fig. a , the most evident effects of Dasatinib in both cell models were represented by a significant down-regulation of the phosphorylation levels of p38 MAPK, ERK1/2 and CREB. In addition, densitometric analysis of the phospho-kinase array demonstrated that Dasatinib also inhibited the phosphorylation levels of several STAT family members (STAT1, STAT2, STAT3, STAT5a/b and STAT6), the most evident effect in both p53 wild-type (EHEB) and p53 mutated (BJAB) cell lines being on STAT2, STAT3 and STAT6 (Fig. b)

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Source Clin Cancer Res, 2011, 17, 762-770. Dasatinib purchased from Selleck
Method Assessment of cell viability and apoptosis
Cell Lines B-CLL patient leukemic cells
Concentrations 2-10 μM
Incubation Time 48 h
Results The Dasatinib+Nutlin-3 combination promotes synergistic cytotoxicity in primary CLL cells as well as in p53 wild-type and p53 deleted/ mutated leukemic cell lines.

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Rating
Source Clin Cancer Res, 2011, 17, 762-770. Dasatinib purchased from Selleck
Method Western blot
Cell Lines Leukemic cell lines
Concentrations 10 μM
Incubation Time 24 h
Results Dasatinib marginally affected both the basal levels of p53 and the accumulation of p53 induced by Nutlin-3 in the p53 wild -type cells (Fig. A).Interestingly, however, levels of both MDM2 and p21 proteins, 2 of the best characterized transcriptional targets of p53, weres significantly (P < 0.05) decreased in cells treated with Dasatinib+ Nutlin-3 with respect to cells treated with Nutlin-3 alone (Fig. B).

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Rating
Source Clin Cancer Res, 2011, 17, 762-770. Dasatinib purchased from Selleck
Method Phospho-kinase array analysis
Cell Lines EHEB cell lines/BJAB cell lines
Concentrations 10 μM
Incubation Time 16 h
Results Although Nutlin-3 had no effects on these pathways, Dasatinib alone as well as Dasatinib+Nutlin-3 markedly inhibited the basal phosphorylation of ERK1/2, p38/MAPK, and Akt . Of interest, the combination of Dasatinib+Nutlin-3 selectively enhanced (P < 0.05) the inhibition of Akt phosphorylation with respect to Dasatinib alone, as validated by Western blot analysis.

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Source Dr Thomas Kruwel of Fraunhofer-Institute for Toxicology and Experimental Medicine-Dasatinib (BMS-354825) purchased from Selleck. Dasatinib purchased from Selleck
Method Cell vability assays
Cell Lines A2C12, Beta D5, Gamma A3, Gamma D12, A549, CaCo2, HepG2 cell lines
Concentrations 0.001-1000 nM
Incubation Time 24/96 h
Results

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Rating
Source Biochem Pharmacol , 2011, 82(10), 1457-1466. Dasatinib purchased from Selleck
Method MTT assay
Cell Lines MOLM-13 cells, HL-60 cells
Concentrations 1-15 μM
Incubation Time 24-72 h
Results Dasatinib and other TKI decreased the viability of the two myeloid cell lines in a dose- and time-dependent manner. Nevertheless, the anti-leukemic efficacy of Dasatinib and other TKI varied considerably in both cell lines.

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Source Cell Res, 2011, 21, 1080-1087. Dasatinib purchased from Selleck
Method Microangiography
Cell Lines embryos
Concentrations 30 μM
Incubation Time
Results MEK1/2 may cooperate with VEGFR to regulate blood vessel lumen diameter. We examined this hypothesis by combining VEGFR inhibitor Sunitinib and MEK1/2 inhibitor U0126. Indeed, U0126 (10 µM) combined with Sunitinib (20 µM) resulted in a reduction of vessel lumen size (Figure F), whereas individually they did not. Combined treatment of another MAP kinase signaling pathway inhibitor Dasatinib (20 µM) with Sunitinib (20 µM) produced a similar phenotype as PP1, whereas each individual inhibitor did not result in any vessel shrinkage even at much higher concentrations ( Figure C).Since there are three major VEGF receptors, it is desirable to determine which receptor is involved in combinatory action with MEK1/2. To address this issue, additional highly selective VEGFR inhibitors PTK787 and ZM323881 were tested. Both of these inhibitors (PTK787 or ZM323881), when individually combined with Dasatinib or U0126, induced a reduction of vessel lumen size (Figure D, E, G, and H).

製品表彰状 (32)

  • Decoupling of tumor-initiating activity from stable immunophenotype in HoxA9-Meis1-driven AML. [Gibbs KD Jr, et al. Cell Stem Cell 2012;10(2):210-7]

    PubMed: 22305570
  • A common rejection module (CRM) for acute rejection across multiple organs identifies novel therapeutics for organ transplantation. [Khatri P, et al. J Exp Med 2013;210(11):2205-21]

    PubMed: 24127489
  • A molecular basis for the association of the HLA-DRB1 locus, citrullination, and rheumatoid arthritis. [Scally SW, et al. J Exp Med 2013;210(12):2569-82]

    PubMed: 24190431
  • Combinatory action of VEGFR2 and MAP kinase pathways maintains endothelial-cell integrity. [Zhong H, et al. Cell Res 2011;21(7):1080-7]

    PubMed: 21423276
  • Amplification of CRKL Induces Transformation and Epidermal Growth Factor Receptor Inhibitor Resistance in Human Non-Small Cell Lung Cancers. [Cheung HW, et al. Cancer Discov 2011;1(7):608-25]

    PubMed: 22586683
  • Dasatinib inhibits proinflammatory functions of mature human neutrophils. [Futosi K, et al. Blood 2012;119(21):4981-91]

    PubMed: 22411867
  • Dasatinib plus Nutlin-3 shows synergistic antileukemic activity in both p53wild-type and p53mutated B chronic lymphocytic leukemias by inhibiting the Akt pathway. [Zauli G, et al. Clin Cancer Res 2011;17(4):762-70]

    PubMed: 21106726
  • STAT5A-mediated SOCS2 expression regulates Jak2 and STAT3 activity following c-Src inhibition in head and neck squamous carcinoma. [Sen B, et al. Clin Cancer Res 2012;18(1):127-39]

    PubMed: 22090359
  • Network analysis identifies an HSP90-central hub susceptible in ovarian cancer. [Liu H, et al. Clin Cancer Res 2013;19(18):5053-67]

    PubMed: 23900136
  • Azacytidine and erlotinib exert synergistic effects against acute myeloid leukemia. [Lainey E, et al. Oncogene 2012;32(37):4331-42]

    PubMed: 23085751
  • VEGFR2 and Src kinase inhibitors suppress Andes virus-induced endothelial cell permeability. [Gorbunova EE, et al. J Virol 2011;85(5):2296-303]

    PubMed: 21177802
  • Andes virus infection of lymphatic endothelial cells causes giant cell and enhanced permeability responses that are rapamycin and vascular endothelial growth factor C sensitive. [Gavrilovskaya IN, et al. J Virol 2012;86(16):8765-72]

    PubMed: 22696643
  • MCL1 down-regulation plays a critical role in mediating the higher anti-leukaemic activity of the multi‐kinase inhibitor Sorafenib with respect to Dasatinib. [Secchiero P, et al. Br J Haematol 2012;157(4):510-4]

    PubMed: 22313359
  • Role of E-cadherin in antimigratory and antiinvasive efficacy of silibinin in prostate cancer cells. [Deep G, et al. Cancer Prev Res (Phila) 2011;4(8):1222-32]

    PubMed: 21546539
  • Effects of the hedgehog inhibitor GDC-0449, alone or in combination with dasatinib, on BCR-ABL-positive leukemia cells. [Okabe S, et al. Stem Cells Dev 2012;21(16):2939-48]

    PubMed: 22642671
  • Cyclophilin D Extramitochondrial Signaling Controls Cell Cycle Progression and Chemokine-Directed Cell Motility. [Tavecchio M, et al. J Biol Chem 2013;288(8):5553-61]

    PubMed: 23303179
  • Role of increased guanosine triphosphate cyclohydrolase-1 expression and tetrahydrobiopterin levels upon T cell activation. [Chen W, et al. J Biol Chem 2011;286(16):13846-51]

    PubMed: 21343293
  • Tyrosine kinase inhibitors for the treatment of acute myeloid leukemia: delineation of anti-leukemic mechanisms of action. [Lainey E, et al. Biochem Pharmacol 2011;82(10):1457-66]

    PubMed: 21664897
  • RON confers lapatinib resistance in HER2-positive breast cancer cells. [Wang Q, et al. Cancer Lett 2013;340(1):43-50]

    PubMed: 23811285
  • IGFBP2/FAK pathway is causally associated with dasatinib resistance in non-small cell lung cancer cells. [Lu H, et al. J Neurochem 2013;12(12):2864-73]

    PubMed: 24130049
  • Exosomes released by K562 chronic myeloid leukemia cells promote angiogenesis in a src-dependent fashion. [Mineo M, et al. Angiogenesis 2012;15(1):33-45]

    PubMed: 22203239
  • Novel, activating KIT-N822I mutation in familial cutaneous mastocytosis. [Wasag B, et al. Exp Hematol 2011;39(8):859-65.e2]

    PubMed: 21689725
  • p38α MAP Kinase Dimers with Swapped Activation Segments and a Novel Catalytic Loop Conformation. [Rothweiler U, et al. J Mol Biol 2011;411(2):474-85]

    PubMed: 21699901
  • Molecular characterization of c-Abl/c-Src kinase inhibitors targeted against murine tumour progenitor cells that express stem cell markers. [Kruewel T, et al. PLoS ONE 2010;5(11):e14143]

    PubMed: 21152443
  • Intracellular Retention of ABL Kinase Inhibitors Determines Commitment to Apoptosis in CML Cells. [Lipka DB, et al. PLoS One 2012;7(7):e40853]

    PubMed: 22815843
  • The immune inhibitory receptor osteoactivin is upregulated in monocyte-derived dendritic cells by BCR–ABL tyrosine kinase inhibitors. [Schwarzbich MA, et al. Cancer Immunol Immunother 2012;61(2):193-202]

    PubMed: 21874302
  • Dasatinib, a small molecule inhibitor of the Src kinase, reduces the growth and activates apoptosis in pre-neoplastic Barrett's esophagus cell lines: Evidence for a noninvasive treatment of high-grade dysplasia. [Inge LJ, et al. J Thorac Cardiovasc Surg 2013;145(2):531-8]

    PubMed: 23142123
  • Anti-leukemic activity of Dasatinib in both p53wild-type and p53mutated B malignant cells. [Bosco R, et al. Invest New Drugs 2012;30(1):417-22]

    PubMed: 20953816
  • Simultaneous quantification of ruxolitinib and nilotinib in rat plasma by LC–MS/MS: Application to a pharmacokinetic study [Sridhar Veeraraghavan J PHARMACEUT BIOMED 2014;10.1016/j.jpba.2014.01.040]

  • Development and Validation of a High-Throughput Intrinsic ATPase Activity Assay for the Discovery of MEKK2 Inhibitors. [Ahmad S, et al. J Biomol Screen 2012;18(4):388-99]

    PubMed: 23134735
  • Direct effect of dasatinib on proliferation and cytotoxicity of natural killer cells in in vitro study. [Uchiyama T, et al. Hematol Oncol 2012;10.1002/hon.2034]

    PubMed: 23108877
  • High-performance liquid chromatography with ultraviolet detection and protein precipitation as a way of quantitative determination of nilotinib with and without internal … [Marek Dziadosz, et al. Journal of Liquid Chromatography & Related Technologies 2012;2503-2510]

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