Temsirolimus (CCI779, NSC683864)

Alias: CCI-779; CCI779; CCI 779; NSC 683864; NSC683864; NSC-683864; Temsirolimus; Brand name: Torisel
Cat No.:V0178 Purity: ≥98%
Temsirolimus (also known as CCI-779, NSC-683864; Torisel), an ester analog of rapamycin, is a potent and specific inhibitor ofmTOR (mammalian target of rapamycin) with potential anticancer activity.
Temsirolimus (CCI779, NSC683864) Chemical Structure CAS No.: 162635-04-3
Product category: mTOR
This product is for research use only, not for human use. We do not sell to patients.
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Purity & Quality Control Documentation

Purity: ≥98%

Product Description

Temsirolimus (also known as CCI-779, NSC-683864; Torisel), an ester analog of rapamycin, is a potent and specific inhibitor of mTOR (mammalian target of rapamycin) with potential anticancer activity. It inhibits mTOR with an IC50 of 1.76 μM in a cell-free assay. Temsirolimus is an ester derivative of rapamycin and has improved pharmacodynamic and pharmacokinetic properties. Temsirolimus, an mTOR inhibitor, reduced cell proliferation in cancer cells where mTOR dysregulates the cell cycle targets. Temsirolimus demonstrated strong antigrowth activity against a panel of eight human breast cancer cell lines, with IC50 values of 0.6, 0.7, and 0.7nM for BT-474, MDA-MB-468, and SKBR-3 cells, respectively. Temsirolimus (trade name: Torisel) was approved by the FDA in May 2007 for the treatment of renal cell carcinoma (RCC).

Biological Activity I Assay Protocols (From Reference)
Targets
mTOR (IC50 = 1.76 μM)
ln Vitro
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) exhibits a modest and selective antiproliferative activity via FKBP12-dependent mechanism, but at low micromolar concentrations (5-15 μM), it can completely inhibit the proliferation of a wide panel of tumor cells by suppressing mTOR signaling in a manner that is FKBP12-independent. Treatment with temsirolimus at micromolar (20 μM), but not nanomolar, concentrations results in a marked reduction in overall protein synthesis and polyribosome disassembly, which is accompanied by a sharp rise in the phosphorylation of the translation elongation factor eEF2 and the translation initiation factor eIF2A.[1] Temsirolimus inhibits cell growth and clonogenic survival in both cells in a concentration-dependent manner, but more potently in PTEN-positive DU145 cells than in PTEN-negative PC-3 cells. It also inhibits the phosphorylation of ribosomal protein S6. [2] Primary human lymphoblastic leukemia (ALL) cells are potently inhibited from proliferating and are induced to undergo apoptosis by temsirolimus (100 ng/mL).[3]
ln Vivo
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.[3] Temsirolimus (20 mg/kg i.p. 5 days/week) significantly slows down the growth of DAOY xenografts compared to controls, delaying it by 160% after 1 week and 240% after 2 weeks. One week of treatment with a single high-dose of temsirolimus (100 mg/kg i.p.) causes a 37% reduction in tumor volume. The growth of rapamycin-resistant U251 xenografts is also 148% delayed by temsirolimus treatment for 2 weeks.[4] Temsirolimus's inhibition of mTOR enhances performance on four distinct behavioral tasks and reduces aggregate formation in a mouse model of Huntington disease. [5] Temsirolimus administration results in significant dose-dependent, antitumor responses against subcutaneous growth of 8226, OPM-2, and U266 xenografts, with ED50 values of 20 mg/kg and 2 mg/kg for 8226 and OPM-2, respectively. These responses are linked to decreased tumor cell growth and inhibition of angiogenesis as well as increased apoptosis and inhibition of proliferation.[6]
Enzyme Assay
Transiently transfecting HEK293 cells with Flag-tagged wild-type human mTOR (Flag-mTOR) DNA constructs. 48 hours later, Flag-mTOR protein is extracted and purified. Purified Flag-mTOR in vitro kinase assays are carried out in 96-well plates in the presence of various Temsirolimus concentrations without FKBP12, and the results are detected using the dissociation-enhanced lanthanide fluorescent immunoassay (DELFIA) method with His6-S6K1 as the substrate. Enzymes are 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). 12 μL of the diluted enzyme and 0.5 μL of temsirolimus are quickly combined in each well. The kinase reaction is started by adding 12.5 μL of ATP and His6-S6K-containing kinase assay buffer to create a final reaction volume of 25 μL that contains 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 before being stopped by adding 25 μL of stop buffer (20 mM Hepes (pH 7.4), 20 mM EDTA, and 20 mM EGTA). A monoclonal anti-P(T389)-p70S6K antibody labeled with Europium-N1-ITC (Eu) (10.4 Eu per antibody) is used for the DELFIA detection of the phosphorylated (Thr-389) His6-S6K at room temperature. Transfer 45 μL of the terminated kinase reaction mixture to a MaxiSorp plate containing 55 μL PBS. Eu-P(T389)-S6K antibody is added to 100 μL of DELFIA buffer at a concentration of 40 ng/mL. With minimal agitation, the antibody binding is continued for an additional hour. The wells are then aspirated and cleaned using PBS with 0.05% Tween 20 (PBST). Each well receives 100 L of DELFIA Enhancement solution before the plates are read using a PerkinElmer Victor model plate reader.
Cell Assay
Temsirolimus is applied to cells in a range of concentrations for 72 hours. Viable cell densities are assessed following treatment using the CellTiter AQ assay kit to measure MTS dye conversion.
Animal Protocol
Cells are implanted in matrigel for the creation of xenografts; matrigel is stored at −20°C and thawed on ice at 4°C for 3 hours prior to use. After being gently resuspended in 1 mL of PBS, the cells are incubated for 5 minutes on ice. Cells are transferred to the tube containing 1 mL of matrigel using a prechilled pipette, and the cell concentration is adjusted to 3×107/mL. Using a 25-gauge needle, the cells (3×106 in 0.1 mL) are injected s.c. into the mice's flanks. When xenografts grew to a size of about 5 mm in diameter, animals are assorted randomLy into groups of 10 mice. The following experiments are conducted: Mice bearing PC-3 tumors are treated with CCI-779 (1, 5, 10, and 20 mg per kg per day), or vehicle solution for 3 or 5 days per week for 3 weeks. Mice bearing DU145 tumors are only treated with CCI-779 (20 mg per kg per day) or vehicle solution for 3 weeks. Mice bearing PC-3 tumors receive the following treatments: (a) control, vehicle solution for CCI-779; (b) chemotherapy alone, mitoxantrone 1.5 mg/kg or docetaxel 10 mg/kg is injected i.p. weekly for 3 doses; (c) CCI-779 alone, 5 or 10 mg/kg is injected i.p. daily, three times a week for 3 weeks; (4) chemotherapy followed by CCI-779.
References

[1]. Cancer Res. 2008 Apr 15;68(8):2934-43.

[2]. Cancer Res. 2005 Apr 1;65(7):2825-31.

[3]. Blood. 2006 Feb 1;107(3):1149-55.

These protocols are for reference only. InvivoChem does not independently validate these methods.
Physicochemical Properties
Molecular Formula
C56H87NO16
Molecular Weight
1030.29
Exact Mass
1029.60249
Elemental Analysis
C, 65.28; H, 8.51; N, 1.36; O, 24.85
CAS #
162635-04-3
Appearance
Solid powder
SMILES
C[C@@H]1CC[C@H]2C[C@@H](/C(=C/C=C/C=C/[C@H](C[C@H](C(=O)[C@@H]([C@@H](/C(=C/[C@H](C(=O)C[C@H](OC(=O)[C@@H]3CCCCN3C(=O)C(=O)[C@@]1(O2)O)[C@H](C)C[C@@H]4CC[C@H]([C@@H](C4)OC)OC(=O)C(C)(CO)CO)C)/C)O)OC)C)C)/C)OC
InChi Key
CBPNZQVSJQDFBE-FUXHJELOSA-N
InChi Code
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
Chemical Name
[(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[30.3.1.04,9]hexatriaconta-16,24,26,28-tetraen-12-yl]propyl]-2-methoxycyclohexyl] 3-hydroxy-2-(hydroxymethyl)-2-methylpropanoate
Synonyms
CCI-779; CCI779; CCI 779; NSC 683864; NSC683864; NSC-683864; Temsirolimus; Brand name: Torisel
HS Tariff Code
2934.99.9001
Storage

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Shipping Condition
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
Solubility Data
Solubility (In Vitro)
DMSO: ~75 mg/mL (~72.8 mM)
Water: <1 mg/mL
Ethanol: ~75 mg/mL (~72.8 mM)
Solubility (In Vivo)
30% PEG400+0.5% Tween80+5% propylene glycol:10mg/mL (Please use freshly prepared in vivo formulations for optimal results.)
Preparing Stock Solutions 1 mg 5 mg 10 mg
1 mM 0.9706 mL 4.8530 mL 9.7060 mL
5 mM 0.1941 mL 0.9706 mL 1.9412 mL
10 mM 0.0971 mL 0.4853 mL 0.9706 mL

*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.

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Working concentration mg/mL;

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Clinical Trial Information
NCT Number Recruitment interventions Conditions Sponsor/Collaborators Start Date Phases
NCT02420613 Active
Recruiting
Drug: Vorinostat
Drug: Temsirolimus
Diffuse Intrinsic Pontine Glioma M.D. Anderson Cancer Center October 5, 2015 Phase 1
NCT01375829 Active
Recruiting
Drug: Ixabepilone
Drug: Temsirolimus
Adult Solid Neoplasm National Cancer Institute
(NCI)
June 27, 2011 Phase 1
NCT02389309 Active
Recruiting
Drug: Dasatinib
Drug: Temsirolimus
Recurrent Brain Neoplasm
Refractory Brain Neoplasm
M.D. Anderson Cancer Center October 5, 2015 Phase 1
NCT01187199 Active
Recruiting
Drug: Bevacizumab
Drug: Temsirolimus
Advanced Cancer M.D. Anderson Cancer Center August 19, 2010 Phase 1
NCT01396408 Active
Recruiting
Drug: Sunitinib
Drug: Temsirolimus
Advanced Rare Tumours Canadian Cancer Trials Group February 9, 2012 Phase 2
Biological Data
  • Temsirolimus (CCI-779, NSC 683864)

    Minimal toxicity of CCI-779 (Temsirolimus) in NOD/SCID mice.2004 Dec 15;104(13):4181-7.

  • Temsirolimus (CCI-779, NSC 683864)

    Antitumor effect of CCI-779.2004 Dec 15;104(13):4181-7.

  • Temsirolimus (CCI-779, NSC 683864)

    Antitumor effects of CCI-779.2004 Dec 15;104(13):4181-7.

  • Temsirolimus (CCI-779, NSC 683864)

    Antiangiogenic effects of CCI-779.2004 Dec 15;104(13):4181-7.


  • Temsirolimus (CCI-779, NSC 683864)

    CCI-779 induces myeloma cell apoptosis.

    Temsirolimus (CCI-779, NSC 683864)

    CCI-779''''s effects on p70S6kinase phosphorylation and cell-cycle regulatory proteins in vivo.2004 Dec 15;104(13):4181-7.


  • Temsirolimus (CCI-779, NSC 683864)

    Temsirolimus (CCI-779, NSC 683864)

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