(1R,2R,4S)-4-[(2R)-2-[(1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18-dihydroxy-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-2,3,10,14,20-pentaoxo-11,36-dioxa-4-azatricyclo[30.3.1.0^{4,9}]hexatriaconta-16,24,26,28-tetraen-12-yl]propyl]-2-methoxycyclohexyl 3-hydroxy-2-(hydroxymethyl)-2-methylpropanoate

• ChemBase编号: 4426
• 分子式: C56H87NO16
• 平均质量: 1030.28708
• 单一同位素质量: 1029.60248571
• SMILES: N12[C@H](C(=O)O[C@H]([C@@H](C[C@H]3C[C@H]([C@@H](CC3)OC(=O)C(CO)(CO)C)OC)C)CC(=O)[C@@H](/C=C(/[C@H]([C@H](C(=O)[C@@H](C[C@@H](/C=C/C=C/C=C(/[C@H](C[C@H]3O[C@@](C(=O)C1=O)([C@@H](CC3)C)O)OC)\C)C)C)OC)O)\C)C)CCCC2
• Canonical SMILES: CO[C@@H]1C[C@@H](CC[C@H]1OC(=O)C(CO)(CO)C)C[C@H]([C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@]2(O)O[C@@H](CC[C@H]2C)C[C@H](OC)/C(=C/C=C/C=C/[C@H](C[C@H](C(=O)[C@@H]([C@@H](/C(=C/[C@H](C(=O)C1)C)/C)O)OC)C)C)/C)C
• InChI: InChI=1S/C56H87NO16/c1-33-17-13-12-14-18-34(2)45(68-9)29-41-22-20-39(7)56(67,73-41)51(63)52(64)57-24-16-15-19-42(57)53(65)71-46(30-43(60)35(3)26-38(6)49(62)50(70-11)48(61)37(5)25-33)36(4)27-40-21-23-44(47(28-40)69-10)72-54(66)55(8,31-58)32-59/h12-14,17-18,26,33,35-37,39-42,44-47,49-50,58-59,62,67H,15-16,19-25,27-32H2,1-11H3/b14-12+,17-13+,34-18+,38-26+/t33-,35-,36-,37-,39-,40+,41+,42+,44-,45+,46+,47-,49-,50+,56-/m1/s1
• InChIKey: CBPNZQVSJQDFBE-FUXHJELOSA-N

名称和登记号

名称

• IUPAC标准名: (1R,2R,4S)-4-[(2R)-2-[(1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18-dihydroxy-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-2,3,10,14,20-pentaoxo-11,36-dioxa-4-azatricyclo[30.3.1.0^{4,9}]hexatriaconta-16,24,26,28-tetraen-12-yl]propyl]-2-methoxycyclohexyl 3-hydroxy-2-(hydroxymethyl)-2-methylpropanoate
• IUPAC传统名: torisel
• 商标名: Torisel
• 别名: CCI-779; temsirolimus; Temsirolimus; Torisel

登记号

• CAS号: 162635-04-3
• PubChem SID: 99443243; 160967858
• PubChem CID: 6918289; 23724530

理论计算性质

ALOGPS 2.1

• 溶解度: 2.35e-03 g/l
• Log P: 4.39
• LOG S: -5.64

JChem

• Acid pKa: 9.96374
• 质子受体: 14
• 质子供体: 4
• LogD (pH = 5.5): 7.1299443
• LogD (pH = 7.4): 7.128776
• Log P: 7.1299596
• 摩尔折射率: 277.0665 cm^3
• 极化性: 108.30001 Å^3
• 极化表面积: 241.96 Å^2
• 可自由旋转的化学键: 11
• 里宾斯基五规则: false

分子性质

理化性质

• 溶解度: DMSO

安全信息

• 保存条件: -20°C

药理学性质

• 作用靶点: mTOR

产品相关信息

• 成盐信息: Free Base

详细说明

DrugBank - DB06287

• Drug Groups: approved; investigational
• Description: Temsirolimus is an intravenous drug for the treatment of renal cell carcinoma (RCC), developed by Wyeth Pharmaceuticals and approved by the FDA in late May 2007, and was also approved by the European Medicines Agency (EMEA) on November 2007. It is a derivative of sirolimus and is sold as Torisel.
• Indication: For the treatment of renal cell carcinoma (RCC). Also investigated for use/treatment in breast cancer, lymphoma (unspecified), rheumatoid arthritis, and multiple myeloma.
• Toxicity: Temsirolimus has been administered to patients with cancer in phase 1 and 2 trials with repeated intravenous doses as high as 220 mg/m2. The risk of several serious adverse events, including thrombosis, bowel perforation, interstitial lung disease (ILD), seizure, and psychosis, is increased with doses of temsirolimus greater than 25 mg.
• Affected Organisms: Humans and other mammals
• Biotransformation: Primarily metabolized by cytochrome P450 3A4 in the human liver. Sirolimus, an equally potent metabolite, is the primary metabolite in humans following IV infusion. Other metabolic pathways observed in in vitro temsirolimus metabolism studies include hydroxylation, reduction and demethylation.
• Absorption: Infused intravenous over 30 - 60 minutes. C_max is typically observed at the end of infusion
• Half Life: Temsirolimus exhibits a bi-exponential decline in whole blood concentrations and the mean half-lives of temsirolimus and sirolimus were 17.3 hr and 54.6 hr, respectively.
• Protein Binding: 87% bound to plasma proteins in vitro at a concentration of 100 ng/ml
• Elimination: Excreted predominantly in feces (76%), 4.6% of drug and metabolites recovered in urine. 17% of drug was not recovered by either route following a 14-day sample collection.
• Distribution: 172 L in whole blood of cancer patients; both temsirolimus and sirolimus are extensive distributed partitioned into formed blood elements
• Clearance: 16.2 L/h (22%)
• References: Wyeth Pharmaceuticals Inc. Torisel? (temsirolimus) injection prescribing information. Philadelphia, PA: 2010 Sep.; Boni J, Leister C, Burns J, Cincotta M, Hug B, Moore L: Pharmacokinetic profile of temsirolimus with concomitant administration of cytochrome p450-inducing medications. J Clin Pharmacol. 2007 Nov;47(11):1430-9. Epub 2007 Oct 3. [Pubmed]
• External Links: Wikipedia; RxList; Drugs.com

Selleck Chemicals - S1044

Research Area

• Description: Soft Tissue Sarcoma,Multiple myeloma,Cancer

Biological Activity

• Description: Temsirolimus (CCI-779, Torisel) is a specific mTOR inhibitor with IC50 of 1.76 μM.
• Targets: mTOR
• IC50: 1.76 μM ^[1]
• In Vitro: Temsirolimus inhibits the phosphorylation of ribosomal protein S6, more potently in PTEN-positive DU145 cells than in PTEN-negative PC-3 cells, and inhibits cell growth and clonogenic survival of both cells in a concentration-dependent manner. ^[5] Temsirolimus (100 ng/mL) potently inhibits proliferation and induces apoptosis in primary human lymphoblastic leukemia (ALL) cells. ^[6] In the absence of FKBP12, Temsirolimus potently inhibits mTOR kinase activity with IC50 of 1.76 μM, similar to that of rapamycin with IC50 of 1.74 μM. Temsirolimus treatment at nanomolar concentrations (10 nM to <5 μm)="" displays="" a="" modest="" and="" selective="" antiproliferative="" activity="" via="" fkbp12-dependent="" mechanism,="" but="" can="" completely="" inhibit="" the="" proliferation="" of="" a="" broad="" panel="" of="" tumor="" cells="" at="" low="" micromolar="" concentrations="" (5-15="" μm),="" involving="" fkbp12-independent="" suppression="" of="" mtor="" signaling.="" temsirolimus="" treatment="" at="" micromolar="" but="" not="" nanomolar="" concentrations="" (20="" μm)="" causes="" a="" marked="" decline="" in="" global="" protein="" synthesis="" and="" disassembly="" of="" polyribosomes,="" accompanied="" by="" rapid="" increase="" in="" the="" phosphorylation="" of="" translation="" elongation="" factor="" eef2="" and="" the="" translation="" initiation="" factor="" eif2a.="">^[1]
• In Vivo: Administration of Temsirolimus (20 mg/kg i.p. 5 days/week) significantly delays the growth of DAOY xenografts by 160% after 1 week and 240% after 2 weeks, compared with controls. Single high-dose of Temsirolimus (100 mg/kg i.p) treatment induces 37% regression of tumor volume within 1 week. Temsirolimus treatment for 2 weeks also delays the growth of rapamycin-resistant U251 xenografts by 148%. ^[2] Inhibition of mTOR by Temsirolimus improves performance on four different behavioral tasks and decreases aggregate formation in a mouse model of Huntington disease. ^[3] Administration of Temsirolimus induces significant dose-dependent, antitumor responses against subcutaneous growth of 8226, OPM-2, and U266 xenografts with ED50 of 20 mg/kg and 2 mg/kg for 8226 and OPM-2, respectively, which are associated with inhibited proliferation and angiogenesis, induction of apoptosis, and reduction in tumor cell size. ^[4] In the NOD/SCID xenograft models with human ALL, Temsirolimus treatment at 10 mg/kg/day produces a decrease in peripheral blood blasts and in splenomegaly ^[6]
• Clinical Trials: A Phase IV study of two different doses of Temsirolimus in patients with mantle cell lymphoma is currently ongoing.

Combination Therapy

• Description: Administration of Temsirolimus (20 mg/kg i.p., 5 days/week for 2 weeks) in combination with cisplatin (5 mg/kg i.p., day 1) induces 1.3 times greater growth inhibition of DAOY xenografts than cisplatin treatment alone. ^[2] Low doses of Temsirolimus (5 mg/kg or 10 mg/kg, 3 days per week for 3 weeks) given between courses of mitoxantrone (1.5 mg/kg) or docetaxe (10 mg/kg) treatment potently increases the growth delay of PC-3 tumors. ^[5] A Phase I study of Temsirolimus plus capecitabine in patients with advanced cancer is currently ongoing.

Protocol

• Protocol: Kinase Assay ^[1]
• In vitro assay of mTOR catalytic activity: The Flag-tagged wild-type human mTOR (Flag-mTOR) DNA constructs are transiently transfected into HEK293 cells. Protein extraction and purification of Flag-mTOR are carried out 48 hours later. In vitro kinase assays of purified Flag-mTOR in the presence of various concentrations of Temsirolimus without FKBP12 are performed in 96-well plate and detected by dissociation-enhanced lanthanide fluorescent immunoassay (DELFIA) using His6-S6K1 as the substrate. Enzymes is first diluted in kinase assay buffer (10 mM Hepes (pH 7.4), 50 mM NaCl, 50 mM β-glycerophosphate, 10 mM MnCl₂, 0.5 mM DTT, 0.25 μM microcystin LR, and 100 μg/mL BSA). To each well, 12 μL of the diluted enzyme is mixed briefly with 0.5 μL Temsirolimus. The kinase reaction is initiated by adding 12.5 μL kinase assay buffer containing ATP and His6-S6K to give a final reaction volume of 25 μL containing 800 ng/mL FLAG-mTOR, 100 μM ATP, and 1.25 μM His6-S6K. The reaction plate is incubated for 2 hours (linear at 1-6 hours) at room temperature with gentle shaking and then terminated by adding 25 μL Stop buffer (20 mM Hepes (pH 7.4), 20 mM EDTA, and 20 mM EGTA). The DELFIA detection of the phosphorylated (Thr-389) His6-S6K is performed at room temperature using a monoclonal anti-P(T389)-p70S6K antibody labeled with Europium-N1-ITC (Eu) (10.4 Eu per antibody). 45 μL of the terminated kinase reaction mixture is transferred to a MaxiSorp plate containing 55 μL PBS. The His6-S6K is allowed to attach for 2 hours after which the wells are aspirated and washed once with PBS. 100 μL of DELFIA buffer with 40 ng/mL Eu-P(T389)-S6K antibody is added. The antibody binding is continued for 1 hour with gentle agitation. The wells are then aspirated and washed four times with PBS containing 0.05% Tween 20 (PBST). 100 μL of DELFIA Enhancement solution is added to each well and the plates are read in a PerkinElmer Victor model plate reader.
• Protocol: Cell Assay ^[1]
• Cell Lines: A549, H157, H460, H446, HCT116, HT29, SW480, DLD1, Caco2, LNCap, DU145, MDA468, MDA231, HEK293, and PC3-MM2
• Concentrations: Dissolved in DMSO, final concentrations ~20 μM
• Incubation Time: 72 hours
• Methods: Cells are exposed to various concentrations of Temsirolimus for 72 hours. After treatment, viable cell densities are determined by MTS dye conversion using CellTiter AQ assay kit.
• Protocol: Animal Study ^[2]
• Animal Models: Female athymic nude mice injected s.c. with DAOY, or U251 cells
• Formulation: Prepared in 100% EtOH as a 50 mg/mL stock solution, and diluted in 5% Tween 80 and 5% polyethylene glycol 400
• Doses: 20 mg/kg
• Administration: Injection daily 5 times per week

References

• References: [1] Shor B, et al. Cancer Res, 2008, 68(8), 2934-2943.
• References: [2] Geoerger B, et al. Cancer Res, 2001, 61(4), 1527-1532.
• References: [3] Ravikumar B, et al. Nat Genet, 2004, 36(6), 585-595.
• References: [4] Frost P, et al. Blood, 2004, 104(13), 4181-4187.
• References: [5] Wu L, et al. Cancer Res, 2005, 65(7), 2825-2831.
• References: [6] Teachey DT, et al. Blood, 2006, 107(3), 1149-1155.

参考文献

• Wyeth Pharmaceuticals Inc. Torisel? (temsirolimus) injection prescribing information. Philadelphia, PA: 2010 Sep.
• Boni J, Leister C, Burns J, Cincotta M, Hug B, Moore L: Pharmacokinetic profile of temsirolimus with concomitant administration of cytochrome p450-inducing medications. J Clin Pharmacol. 2007 Nov;47(11):1430-9. Epub 2007 Oct 3. Pubmed
• Ravikumar B, et al. Nat Genet, 2004, 36(6), 585-595.
• Wu L, et al. Cancer Res, 2005, 65(7), 2825-2831.
• Frost P, et al. Blood, 2004, 104(13), 4181-4187.
• Shor B, et al. Cancer Res, 2008, 68(8), 2934-2943.
• Geoerger B, et al. Cancer Res, 2001, 61(4), 1527-1532.
• Teachey DT, et al. Blood, 2006, 107(3), 1149-1155.