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English name: Everolimus
CAS No. : 159351-69-6
Molecular formula: C53H83NO14
Molecular weight: 958.22
EINECS number: 621-003-9
Related categories:
Heterocyclic ring type; everolimus; Drug substance intermediates; Signal transduction pathway kinase inhibitors; crude drug; Microbial metabolites; Medical intermediates; inhibitor; Control-impurity control; materia medica; Scientific research reagent; antitumor drug; acridine; Fermentation class; raw material; Small-molecule inhibitors; Small-molecule inhibitors, natural products; Pharmaceutical API; Organic raw materials; Akt; antineoplastic; Control article-Traditional Chinese medicine control article; chemical intermediate; chemical raw material; Impurity control article; chemical reagent; Other categories; Drug substance and intermediates; Organic and chemical raw materials; Daily-use chemicals; Everolimus Impurities; chemical raw material; Clinical test standard substance; AllInhiChemicalbookbitors; Inhibitors; Intermediates&FineChemicals; Pharmaceuticals; Inhibitor; Antineoplasticproteinkinaseinhibitors; mTORinhibitor; Certican, Zortress, Afinitor; Anti-cancer&immunity; PI3K/Akt/mTOR; mTOR; PI3K; Everolimus; API
The Mol file: 159351-69-6.mol.
Structural formula:
Nature of everolimus
melting point:NA
Boiling point: 998.7 ± 75.0 C (Predicted)
Density: 1.18±0.1g/cm3 (Predicted) flash point of 2℃
Storage conditions: -20 C
Solubility: soluble in DMSO (up to 100 mg/ml) or ethanol (up to 100 mg/ml).
Form: solid
Aciity coefficient (pK a): 10.40 ± 0.70 (Predicted)
Color: white
Water solubility:Soluble in dimethysulfoxide,ethanol and chloroform. Slightly soluble in water.
Stability: Hygroscopicity
InChIKey:HKVAMNSJSFKALM-GKUWKFKPSA-N
Sirolimus derivatives
Everolimus is a derivative of sirolimus, also known as 40-O- (2-hydroxyethyl) -rapamycin, or 40-O- (2-hydroxyethyl) -sirolimus, belongs to the cell communication to prevent the growth of tumor cell kinase drugs, is an oral mammalian rapamycin (mTOR) inhibitor, the main clinical Chemicalbook used to prevent rejection after kidney transplantation and heart transplantation. It can also be used to treat patients with advanced kidney cancer who have used two inhibitory vascular endothelial growth factor receptor kinase inhibitors, Sutent (Pfizer) and Nexavar (Bayer), with minor side effects.
Sunitinib and sorafenib are multiple kinase inhibitors (acting on a variety of cellular targets), while everolimus blocks the mammalian target of rapamycin (mTOR) and interferes with the growth, differentiation, and metabolism of cancer cells. This mTOR pathway is dysregulated within some human tumors. Everolimus binds to the intracellular protein FKBP-12 to form an inhibitory complex, thereby inhibiting mTOChemicalbookR kinase activity, while simultaneously reducing the downstream effector of mTOR S6 ribosomal protein kinase (S6K1) and the eukaryotic elongation factor 4E binding protein (4E-BP). In addition, everolimus inhibited the expression of hypoxia-inducible factor (e. g., HIF-1) and reduced the expression of vascular endothelial growth factor (VE GF), both in vitro and in vivo studies showed to reduce cell proliferation, angiogenesis and glucose uptake.
Remarks
1.The mTOR is a serine-threonine kinase, a downstream product of P13K / AKT.
2.and sirolimus is also known as rapamycin.
Use
Everolimus macrolide immunosuppressants; everolimus is a derivative of rapamycin. Everolimus inhibits cytokine-mediated lymphocyte proliferation.
Mechanism of action
Everolimus can bind to the intracellular protein FKBP12 to form the inhibitory complex mTORC1, which suppresses the activity of mTOR. Inhibition of mTOR signaling can lead to reduce the activity of the transcriptional regulator S6 ribosomal protein kinase (S6K1) and Chemicalbook eukaryotic elongation factor 4E binding protein (4E-BP), thus interfering with the translation and synthesis of cell cycle, angiogenesis, glycolysis and other related proteins. In addition, everolimus has certain antitumor efficacy and can inhibit glycolysis of solid tumors in vitro and in vivo.
Target molecule of rapamycin
Activation of the rapamycin target molecule (mTOR) promotes the proliferation and survival of tumor cells, and also causes angiogenic pathway signaling in endothelial cells. The product of rapamycin and intracellular protein binding is- -FK506-bindingprotein12 (FKBP12), and the resulting protein drug complex can inhibit the activity of mTOR kinase. Rapamycin also has immunosuppressive, antifungal, antiviral, vascular protection and anti-tumor activity, but its main application is to take its Chemicalbook immunosuppressive effect, which was approved by the FDA for anti-rejection therapy in organ transplantation in 1999. Many derivatives of rapamycin have been synthesized to improve its drug properties, and these efforts have led to the discovery and study of intravenous use of tuxel (temsirolimus) and everolimus (everolimus) for renal cancer. In 2003 everolimus was approved in Europe for therapeutic rejection after organ transplantation and brought to market under the trade name Certican.
Treatment of advanced kidney cancer and kidney cancer
It accounts for 2-3% of cancer. In the early stage, renal cancer is mainly surgery, while in the late stage, chemotherapy is mainly used, and the response to chemotherapy and radiotherapy is often poor. Chemicalbook In fact, the use of interleukin 2 alone or combined with alpha interferon is limited in its clinical use due to its toxicity and generally poor treatment response.
Renal cell carcinoma is the most common type of renal cancer and occurs from renal tubular epithelial cells. Usually, cancer cells in such patients are resistant to standard therapies such as radiotherapy and chemotherapy, allowing most people to treat them with the removal of renal Chemicalbook. If the patient's cancerous site is limited to the kidney, 60-70% of the human survival period can reach 5 years, but once the cancer cells develop metastasis, the patient's survival will be greatly reduced.
On March 30,2009, Novartis's original immunosuppressive drug everolimus (everolimus, Afinitor) was approved by the US FDA for kidney cancer. Results Chemicalbook showed that everolimus significantly increases progression-free survival in cancer patients, and everolimus provides a new treatment option for patients with advanced renal cell carcinoma who failed to treatment with sunitinib or sorafenib.
In August 2009, the European Commission approved Afinitor (everolimus) tablets produced by Novartis for the treatment of patients with advanced renal cell cancer (RCC). The European Society of Medical Oncology, the European Urological Society (EAU), the Spanish Oncology Group (SOGChemicalbookUG), the European Organization for Cancer Research and Treatment (EORTC), the European Society of Medical Oncology (ESMO), and recommended Afinitor as a second-line treatment for patients with advanced renal cancer.
Bioactivity
Everolimus (RAD001, SDZ-RAD) is an mTOR inhibitor that acts on FKBP12 and IC50 is 1.6-2.4nM in the Chemicalbook cell-free assay. Everolimus can induce apoptosis and autophagy and inhibit the proliferation of tumor cells.
Target spot
Target Value
FKBP12: 1.6-2.4 nM (Cell-free assay)
mTOR (FKBP12) :1.6 nM-2.4 nM (Cell-free assay)
In vitro study
In vitro, Everolimus has inhibitory immune activity compared to Rapamycin. Everolimus Competitively bound with immobilized FK506 to biotinylated FKBP12, IC50 as 1.6nM-2.4nM and acting on spleen cells of BALB / c and CBA mice to inhibit bidirectional MLR and IC50 as 0.12nM-1.8nM. Everolimus Acting on VE GF-induced HUVEC proliferation and bF GF-induced HUVEC proliferation, with antiangiogenic / vascular effect of Chemicalbook with IC50 of 0.12 nM and 0.8 nM, respectively. The latest study showed that Everolimus inhibited all cells and stem cells of BT474 cell line and primary breast cancer cells, with an IC50 of 156 nM of all cells of primary breast cancer and 71 nM of BT474 cells. In addition, the combination of Everolimus and Trastuzumab significantly promoted the inhibition effect on the growth of tumor stem cells, increasing the inhibition rate by more than 50%.
In vivo research
Everolimus (0.1 to 10mg / kg) inhibits primary growth and lymph node metastasis in B16 / BL6 melanoma, accompanied by a decrease in total vessel number Chemicalbook, a dose-dependent effect. Everolimus Animal model of BT474 stem cell graft compared to control (698mm).
Security information
Hazgoods signs: T, Xn, F
Hazard category code: 48 / 25-36-20 / 21 / 22-11
Safety description: 45-36 / 37-26-16
Dangerous Goods Transport No.: UN 1648 3 / PGII
WGK Germany:2
F:10
Customs code: 29349990
Toxic substance data: 159351-69-6 (Hazardous Substances Data)
MSDS information
https://www.biosynergypharm.com/