EasySep™小鼠TIL（CD45）正选试剂盒
产品号 #73532_C
酪氨酸激酶抑制剂；抑制VEGFR1、KDR、FLT-4、EGFR、FGFR、ABL、RET和SRC
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总览
Vandetanib（凡德他尼）是一种多激酶抑制剂，主要靶向受体酪氨酸激酶，例如血管内皮生长因子受体（VEGFR1、KDR和FLT4）、表皮生长因子受体（EGFR）和成纤维细胞生长因子受体（FGFR；Morabito 等人）。它最强效抑制KDR，IC₅₀值为40 nM。它还能抑制非受体酪氨酸激酶，例如RET、ABL和SRC，以及多种丝氨酸/苏氨酸激酶（Carlomagno et al.; Hennequin et al.; Kiselyov et al.; Levinson & Boxer）。
癌症研究
·抑制小鼠异种移植模型中的肿瘤生长，包括RET/PTC乳头状甲状腺癌和肺癌（Hennequin et al.; Carlomagno et al.）。
·抑制多种癌细胞系中的血管生成、细胞生长和转移（Morabito et al.; Wedge et al.）。
细胞类型
癌细胞及细胞系
种属
人，小鼠，非人灵长类，其他物种，大鼠
研究领域
癌症
CAS 编号
443913-73-3
化学式
C₂₂H₂₄BrFN₄O₂
纯度
≥98%
通路
酪氨酸激酶
靶点
ABL，EGFR，FGFR，FLT4，KDR，RET，SRC，VEGFR1
产品说明书及文档
请在《产品说明书》中查找相关支持信息和使用说明，或浏览下方更多实验方案。
相关材料与文献
技术资料 (2)
文献 (6)
Novel 4-anilinoquinazolines with C-7 basic side chains: design and structure activity relationship of a series of potent, orally active, VEGF receptor tyrosine kinase inhibitors.
Journal of medicinal chemistry 2002
Abstract
We have previously shown that 4-anilinoquinazolines can be potent inhibitors of vascular endothelial growth factor (VEGF) receptor (Flt-1 and KDR) tyrosine kinase activity. A novel subseries of 4-anilinoquinazolines that possess basic side chains at the C-7 position of the quinazoline nucleus have been synthesized. This subseries contains potent,nanomolar inhibitors of KDR (median IC(50) 0.02 microM,range 0.001-0.04 microM),which are comparatively less potent vs Flt-1 tyrosine kinase (median IC(50) 0.55 microM,range 0.02-1.6 microM). The compounds also retain some inhibitory activity against the tyrosine kinase associated to the endothelial growth factor receptor (EGFR) (median IC(50) 0.2 microM,range 0.075-0.8 microM) but demonstrate selectivity vs that associated to the FGF receptor 1 (median IC(50) 2.5 microM,range 0.9-19 microM). This selectivity profile is also evident in a growth factor-stimulated human endothelial cell (HUVEC) proliferation assay (i.e.,inhibition of VEGF textgreater EGF textgreater FGF),with inhibition of VEGF-induced proliferation being achieved at nanomolar concentrations (median IC(50) 0.06 microM). Further examination of compound 2 (ZD6474) in recombinant enzyme assays revealed excellent selectivity for the inhibition of KDR tyrosine kinase (IC(50) 0.04 microM) vs the kinase activity of erbB2,MEK,CDK-2,Tie-2,IGFR-1R,PDK,PDGFRbeta,and AKT (IC(50) range: 1.1 to textgreater100 microM). Anilinoquinazolines possessing basic C-7 side chains exhibited markedly improved aqueous solubility over previously described anilinoquinazolines possessing neutral C-7 side chains (up to 500-fold improvement at pH 7.4). In addition,aqueous solubility of the neutral fraction present at pH 7.4 of the basic subseries of anilinoquinazoline proved to be higher than that of the neutral analogue 1 (ZD4190). Oral administration of representative compounds to mice (50 mg/kg) produced plasma levels between 0.2 and 3 microM at 24 h after dosing. Our development candidate 2 demonstrated a very attractive in vitro profile combined with excellent solubility (330 microM at pH 7.4) and good oral bioavailability in rat and dog (textgreater 80 and textgreater 50%,respectively). This compound demonstrated highly significant,dose-dependent,antitumor activity in athymic mice. Once daily oral administration of 100 mg/kg of compound 2 for 21 days inhibited the growth of established Calu-6 lung carcinoma xenografts by 79% (P textless 0.001,Mann Whitney rank sum test),and substantial inhibition (36%,P textless 0.02) was evident with 12.5 mg/kg/day.
ZD6474 inhibits vascular endothelial growth factor signaling, angiogenesis, and tumor growth following oral administration.
Cancer research 2002
Abstract
ZD6474 [N-(4-bromo-2-fluorophenyl)-6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy]quinazolin-4-amine]is a potent,p.o. active,low molecular weight inhibitor of kinase insert domain-containing receptor [KDR/vascular endothelial growth factor receptor (VEGFR) 2] tyrosine kinase activity (IC(50) = 40 nM). This compound has some additional activity versus the tyrosine kinase activity of fms-like tyrosine kinase 4 (VEGFR3;IC(50) = 110 nM) and epidermal growth factor receptor (EGFR/HER1; IC(50) = 500 nM) and yet demonstrates selectivity against a range of other tyrosine and serine-threonine kinases. The activity of ZD6474 versus KDR tyrosine kinase translates into potent inhibition of vascular endothelial growth factor-A (VEGF)-stimulated endothelial cell (human umbilical vein endothelial cell) proliferation in vitro (IC(50) = 60 nM). Selective inhibition of VEGF signaling has been demonstrated in vivo in a growth factor-induced hypotension model in anesthetized rat: administration of ZD6474 (2.5 mg/kg,i.v.) reversed a hypotensive change induced by VEGF (by 63%) but did not significantly affect that induced by basic fibroblast growth factor. Once-daily oral administration of ZD6474 to growing rats for 14 days produced a dose-dependent increase in the femoro-tibial epiphyseal growth plate zone of hypertrophy,which is consistent with inhibition of VEGF signaling and angiogenesis in vivo. Administration of 50 mg/kg/day ZD6474 (once-daily,p.o.) to athymic mice with intradermally implanted A549 tumor cells also inhibited tumor-induced neovascularization significantly (63% inhibition after 5 days; P textless 0.001). Oral administration of ZD6474 to athymic mice bearing established (0.15-0.47 cm(3)),histologically distinct (lung,prostate,breast,ovarian,colon,or vulval) human tumor xenografts or after implantation of aggressive syngeneic rodent tumors (lung,melanoma) in immunocompetent mice,produced a dose-dependent inhibition of tumor growth in all cases. Statistically significant antitumor activity was evident in each model with at least 25 mg/kg ZD6474 once daily (P textless 0.05,one-tailed t test). Histological analysis of Calu-6 tumors treated with 50 mg/kg/day ZD6474 for 24 days showed a significant reduction (textgreater70%) in CD31 (endothelial cell) staining in nonnecrotic regions. ZD6474 also restrained growth of much larger (0.9 cm(3) volume) Calu-6 lung tumor xenografts and induced profound regression in established PC-3 prostate tumors of 1.4 cm(3) volume. ZD6474 is currently in Phase I clinical development as a once-daily oral therapy in patients with advanced cancer.
ZD6474, an orally available inhibitor of KDR tyrosine kinase activity, efficiently blocks oncogenic RET kinases.
Cancer research 2002 DEC
Abstract
RET/papillary thyroid carcinoma (PTC) oncogenes,generated by recombination of the tyrosine kinase-encoding domain of RET with different heterologous genes,are prevalent in papillary carcinomas of the thyroid. Point mutations of RET cause multiple endocrine neoplasia type 2 (MEN2) familial cancer syndrome and are found in sporadic medullary thyroid carcinomas. Here,we show that ZD6474,a low molecular weight tyrosine kinase inhibitor,blocks the enzymatic activity of RET-derived oncoproteins at a one-half maximal inhibitory concentration of 100 nM. ZD6474 blocked in vivo phosphorylation and signaling of the RET/PTC3 and RET/MEN2B oncoproteins and of an epidermal growth factor (EGF)-activated EGF-receptor/RET chimeric receptor. RET/PTC3-transformed cells-treated ZD6474 lost proliferative autonomy and showed morphological reversion. ZD6474 prevented the growth of two human PTC cell lines that carry spontaneous RET/PTC1 rearrangements. Finally,it blocked anchorage-independent growth of RET/PTC3-transformed NIH3T3 fibroblasts and the formation of tumors after injection of NIH-RET/PTC3 cells into nude mice. Thus,targeting RET oncogenes with ZD6474 might offer a potential treatment strategy for carcinomas sustaining oncogenic activation of RET.
更多信息
| 物种 | 人, 其它物种, 大鼠, 小鼠, 非人灵长类 |
|---|---|
| Cas Number | 443913-73-3 |
| Chemical Formula | C₂₂H₂₄BrFN₄O₂ |
| 纯度 | ≥ 98% |
| Target | ABL, EGFR, FGFR, FLT4, KDR, RET, SRC, VEGFR1 |
| Pathway | Tyrosine Kinase |
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