产品号 #73122_C
mTOR pathway inhibitor; Inhibits FKBP-12
概述
Everolimus is an inhibitor of the mammalian target of rapamycin (mTOR). It is a hydroxyethyl ether-substituted derivative of rapamycin with improved pharmacokinetic and pharmacodynamic properties. It inhibits both mTORC1 and mTORC2 complexes by binding to FK506-binding protein (FKBP-12), which then binds to mTOR, leading to complex destabilization and blocked kinase function (Zeng et al.; Lebwohl et al.; Sedrani et al.; Huang & Houghton).
CANCER RESEARCH
· Inhibits cell proliferation, metabolism, and angiogenesis in a variety of cancers using in vitro and in vivo models (Zhu et al.; Lane et al.; O’Reilly et al.; Lebwohl et al.).
IMMUNOLOGY
· Acts as an immunosuppressive agent in the context of organ transplantation (Lebwohl et al.; Wullschleger et al.).
Cell Type
Cancer Cells and Cell Lines
Species
Human, Mouse, Non-Human Primate, Other, Rat
Area of Interest
Cancer, Immunology, Transplantation Research
CAS Number
159351-69-6
Chemical Formula
C₅₃H₈₃NO₁₄
Purity
≥ 95%
Pathway
mTOR
Target
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.
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