产品号 #73122_C
mTOR通路抑制剂；抑制FKBP-12
总览
依维莫司是一种哺乳动物雷帕霉素靶蛋白（mTOR）抑制剂。它是一种羟乙基醚取代的雷帕霉素衍生物，具有更优的药代动力学和药效学性质。它通过结合FK506结合蛋白（FKBP-12）结合，随后该复合物与 mTOR 结合，从而抑制 mTORC1 和 mTORC2 复合物，导致复合物不稳定并阻断激酶功能(Zeng等人；Lebwohl等人；Sedrani等人；Huang & Houghton)。
癌症研究
·在体外和体内模型中，抑制多种癌症中的细胞增殖、代谢和血管生成（Zhu等人；Lane等人；O 'Reilly等人；Lebwohl等人)。
免疫学
·在器官移植背景下，Everolimus 可作为免疫抑制剂使用（Lebwohl 等人；Wullschleger 等人）。
细胞类型
癌细胞及细胞系
种属
人，小鼠，非人灵长类，其它细胞系，大鼠
研究领域
癌症，免疫，移植研究
CAS 编号
159351-69-6
化学式
C₅₃H₈₃NO₁₄
纯度
≥ 95 %
通路
mTOR
靶点
FKBP-12
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 (3)
Publications (7)
Development of everolimus, a novel oral mTOR inhibitor, across a spectrum of diseases. Annals of the New York Academy of Sciences 2013
Abstract
Everolimus is a potent, oral inhibitor of the mammalian target of rapamycin (mTOR) that has been investigated in multiple clinical development programs since 1996. A unique collaboration between academic and pharmaceutical experts fostered research that progressed rapidly, with simultaneous indication findings across numerous tumor types. Initially developed for the prophylaxis of organ transplant rejection, everolimus has demonstrated efficacy and safety for the treatment of patients with various types of cancer (renal cell carcinoma, neuroendocrine tumors of pancreatic origin, and breast cancer) and for adult and pediatric patients with tuberous sclerosis complex. The FDA approval of everolimus for these diseases has addressed several unmet medical needs and is widely accepted by the medical community where treatment options may be limited. An extensive clinical development program is ongoing to establish the role of everolimus as monotherapy, or in combination with other agents, in the treatment of a broad spectrum of malignancies.
Antitumor effect of the mTOR inhibitor everolimus in combination with trastuzumab on human breast cancer stem cells in vitro and in vivo. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 2012
Abstract
This study evaluated the effects of a mammalian target of mTOR inhibitor everolimus alone or in combination with trastuzumab on stem cells from HER2-overexpressing primary breast cancer cells and the BT474 breast cancer cell line in vitro and in vivo. For the in vitro studies, we sorted ESA(+)CD44(+)CD24(-/low) cells as stem cells from primary breast cancer cells and BT474 cells using flow cytometry. The MTT assay was used to quantify the inhibitory effect of the drugs on total cells and stem cells specifically. Stem cell apoptosis, cell cycle distributions, and their tumorigenicity after treatment were investigated by flow cytometry or soft agar colony formation assays. For the in vivo studies, BALB/c mice were injected with BT474 stem cells, and the different treatments were administered. After necropsy, the expression of Ki67, CD31, AKT1, and phospho-AKT (Thr308) was analyzed by immunohistochemistry. For the in vitro studies, Treatment with everolimus resulted in stem cell growth inhibition in a dose-dependent manner. The combination of everolimus with trastuzumab was more effective at inhibiting cell growth (P textless 0.001) and tumorigenicity (P textless 0.001) compared with single-agent therapy. In addition, an increase in G1 cell cycle arrest and an increased population of cells in early apoptosis were seen in the combination treatment group compared with either of the single-agent groups (P textless 0.01). For the in vivo studies, everolimus plus trastuzumab therapy was much more effective at reducing tumor volume in mice compared with either single agent alone (P textless 0.05). Compared with everolimus alone, the combination of everolimus and trastuzumab reduced the expression of Ki67, AKT1, and phospho-AKT (Thr308) (P textless 0.05). We conclude that everolimus has effective inhibitory effects on HER2-overexpressing stem cells in vitro and vivo. Everolimus plus trastuzumab is a rational combination treatment that may be promising in human clinical trials.
mTOR inhibitor RAD001 (everolimus) has antiangiogenic/vascular properties distinct from a VEGFR tyrosine kinase inhibitor. Clinical cancer research : an official journal of the American Association for Cancer Research 2009
Abstract
PURPOSE: Comparison of the antiangiogenic/vascular properties of the oral mammalian target of rapamycin (mTOR) inhibitor RAD001 (everolimus) and the vascular endothelial growth factor receptor (VEGFR) inhibitor vatalanib (PTK/ZK). EXPERIMENTAL DESIGN: Antiproliferative activity against various tumor histotypes and downstream effects on the mTOR pathway were measured in vitro. In vivo, antitumor activity, plasma, and tumor RAD001 levels were measured. Activity in several different angiogenic/vascular assays in vitro and in vivo was assessed and compared with PTK/ZK. RESULTS: RAD001 inhibited proliferation in vitro (IC50 valuestextless1 nmol/L to textgreater1 micromol/L), and in sensitive and insensitive tumor cells, pS6 kinase and 4E-BP1 were inhibited. Activity in vitro did not correlate with activity in vivo and significant responses were seen in tumors with IC50 valuestextgreater10-fold higher than tumor RAD001 concentrations. In vitro, RAD001 inhibited the proliferation of VEGF-stimulated and fibroblast growth factor-stimulated human endothelial cells but not dermal fibroblasts and impaired VEGF release from both sensitive and insensitive tumor cells but did not inhibit migration of human endothelial cells. In vivo, in tumor models derived from either sensitive or insensitive cells, RAD001 reduced Tie-2 levels, the amount of mature and immature vessels, total plasma, and tumor VEGF. RAD001 did not affect blood vessel leakiness in normal vasculature acutely exposed to VEGF nor did it affect tumor vascular permeability (Ktrans) as measured by dynamic contrast-enhanced magnetic resonance imaging. However, the pan-VEGFR inhibitor PTK/ZK inhibited endothelial cell migration and vascular permeability but had less effect on mature vessels compared with RAD001. CONCLUSIONS: VEGFR and mTOR inhibitors show similar but also distinct effects on tumor vascular biology, which has implications for their clinical activity alone or in combination.
更多信息
| Species | Human, Mouse, Non-Human Primate, Other, Rat |
|---|---|
| Cas Number | 159351-69-6 |
| Chemical Formula | C₅₃H₈₃NO₁₄ |
| Purity | ≥ 95% |
| Target | FKBP-12 |
| Pathway | mTOR |
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