产品号 #73082_C
酪氨酸激酶抑制剂；抑制ABL，SRC，LCK和YES
达沙替尼是一种有效的ATP竞争性酪氨酸激酶抑制剂。它对SRC/ABL激酶具有特异性，例如ABL，SRC，LCK和YES，其IC₅₀值分别为; <1.0,0.5,0.4和0.5 nM，同时对KIT也具有活性（IC₅₀ = 5.0 nM）(Lombardo等人；Davis等人)。达沙替尼是第二代癌基因酪氨酸激酶BCR-ABL抑制剂，其效价是伊马替尼的325倍，并且还能够抑制伊马替尼耐药的BCR-ABL突变体（Tokarski等人）。在10 μM浓度下筛选时，它还抑制大量其他激酶的活性（148种测试激酶中的76个）（Carter等人）。
癌症研究
·抑制来自慢性髓性白血病（CML）、前列腺、乳腺和结肠肿瘤的细胞系的增殖（Lombardo等人）。
·抑制携带伊马替尼耐药BCR-ABL突变的细胞增殖（Shah等人）。
·在异种移植裸鼠前列腺癌模型中，抑制肿瘤生长和淋巴结转移的发展（Park等人）。
·诱导甲状腺癌细胞的细胞周期阻滞和细胞凋亡，并抑制甲状腺癌细胞的生长（Chan等人）。
·抑制真皮成纤维细胞细胞外基质蛋白的产生，并防止博来霉素诱导的小鼠纤维化的发生(Distler & Distler；Akhmetshina等人)。
癌症研究
·抑制来自慢性髓性白血病（CML）、前列腺、乳腺和结肠肿瘤的细胞系的增殖（Lombardo等人）。
·抑制携带伊马替尼耐药BCR-ABL突变的细胞增殖（Shah等人）。
·在异种移植裸鼠前列腺癌模型中，抑制肿瘤生长和淋巴结转移的发展（Park等人）。
·诱导甲状腺癌细胞的细胞周期阻滞和细胞凋亡，并抑制甲状腺癌细胞的生长（Chan等人）。
·抑制真皮成纤维细胞细胞外基质蛋白的产生，并防止博来霉素诱导的小鼠纤维化的发生(Distler & Distler；Akhmetshina等人)。
Protocols and Documentation
Find supporting information and directions for use in the Product Information Sheet or explore additional protocols below.
Resources and Publications
Educational Materials (2)
Publications (9)
Targeted inhibition of Src kinase with dasatinib blocks thyroid cancer growth and metastasis. Clinical cancer research : an official journal of the American Association for Cancer Research 2012
Abstract
PURPOSE: There are no effective therapies for patients with poorly differentiated papillary thyroid cancer (PTC) or anaplastic thyroid cancer (ATC), and metastasis to the bone represents a significantly worse prognosis. Src family kinases (SFKs) are overexpressed and activated in numerous tumor types and have emerged as a promising therapeutic target, especially in relation to metastasis. We recently showed that Src is overexpressed and activated in thyroid cancer. We therefore tested whether inhibition of Src with dasatinib (BMS-354825) blocks thyroid cancer growth and metastasis. EXPERIMENTAL DESIGN: The effects of dasatinib on thyroid cancer growth, signaling, cell cycle, and apoptosis were evaluated in vitro. The therapeutic efficacy of dasatinib was further tested in vivo using an orthotopic and a novel experimental metastasis model. Expression and activation of SFKs in thyroid cancer cells was characterized, and selectivity of dasatinib was determined using an Src gatekeeper mutant. RESULTS: Dasatinib treatment inhibited Src signaling, decreased growth, and induced cell-cycle arrest and apoptosis in a subset of thyroid cancer cells. Immunoblotting showed that c-Src and Lyn are expressed in thyroid cancer cells and that c-Src is the predominant SFK activated. Treatment with dasatinib blocked PTC tumor growth in an orthotopic model by more than 90% (P = 0.0014). Adjuvant and posttreatment approaches with dasatinib significantly inhibited metastasis (P = 0.016 and P = 0.004, respectively). CONCLUSION: These data provide the first evidence that Src is a central mediator of thyroid cancer growth and metastasis, indicating that Src inhibitors may have a higher therapeutic efficacy in thyroid cancer, as both antitumor and antimetastatic agents.
Comprehensive analysis of kinase inhibitor selectivity. Nature biotechnology 2011
Abstract
We tested the interaction of 72 kinase inhibitors with 442 kinases covering textgreater80% of the human catalytic protein kinome. Our data show that, as a class, type II inhibitors are more selective than type I inhibitors, but that there are important exceptions to this trend. The data further illustrate that selective inhibitors have been developed against the majority of kinases targeted by the compounds tested. Analysis of the interaction patterns reveals a class of 'group-selective' inhibitors broadly active against a single subfamily of kinases, but selective outside that subfamily. The data set suggests compounds to use as tools to study kinases for which no dedicated inhibitors exist. It also provides a foundation for further exploring kinase inhibitor biology and toxicity, as well as for studying the structural basis of the observed interaction patterns. Our findings will help to realize the direct enabling potential of genomics for drug development and basic research about cellular signaling.
Intracellular tyrosine kinases as novel targets for anti-fibrotic therapy in systemic sclerosis. Rheumatology (Oxford, England) 2008
Abstract
Tissue fibrosis is a major cause of death in SSc, but therapies that target selectively fibrosis are not yet available for routine clinical use. Recent pre-clinical studies suggest that selective tyrosine kinase inhibitors that target c-Abl, PDGF receptor or Src kinases might be promising targets for anti-fibrotic approaches. Dual inhibition of c-Abl and PDGF receptor by imatinib and nilotinib, and inhibition of Src kinases either selectively by SU6656 or in combination with c-Abl and PDGF by dasatinib exerted potent anti-fibrotic effects. Imatinib, nilotinib, dasatinib and SU6656 reduced dose-dependently the synthesis of extracellular matrix protein in human dermal fibroblasts in vitro and prevented fibrosis in the mouse model of bleomycin-induced skin fibrosis. Clinical data from patients with chronic myelogenous leukaemia suggest that imatinib, nilotinib and dasatinib are well tolerated. Based on the promising pre-clinical data, imatinib is currently evaluated in clinical trials for the treatment of fibrosis in SSc and trials with other tyrosine kinase inhibitors are in preparation.
更多信息
| Species | Human, Mouse, Non-Human Primate, Other, Rat |
|---|---|
| Cas Number | 302962-49-8 |
| Chemical Formula | C₂₂H₂₆ClN₇O₂S |
| Purity | ≥ 98% |
| Target | ABL, LCK, SRC |
| Pathway | Tyrosine Kinase |
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翻译:Nilotinib酪氨酸激酶抑制剂；抑制BCR/ABL和ABL
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翻译:Vandetanib酪氨酸激酶抑制剂；抑制VEGFR1， KDR, FLT-4， EGFR， FGFR， ABL， RET和SRC
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