17-AAG (Tanespimycin) 化学構造
分子量: 585.69

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Quality Control & MSDS

製品説明

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製品の説明

生物活性

製品説明 17-AAG (Tanespimycin)は、5nMのIC50による強力な熱ショックタンパク質90(Hsp90)阻害剤です。
ターゲット HSP90
IC50 5 nM [1]
In vitro試験 17-AAG, an analog of geldanamycin, exhibits greater than 100 times higher binding affinity for Hsp90 derived from HER-2-overexpressing cancer cells (BT474, N87, SKOV3 and SKBR3) or BT474 breast carcinoma cells with IC50 values of 5-6 nM. [1] 17-AAG causes the degradation of HER2, HER3, Akt, and both mutant and wild-type androgen receptor (AR), leading to the RB-dependent G1 growth arrest of prostate cancer cells such as LNCaP, LAPC-4, DU-145, and PC-3 with IC50 values of 25-45 nM. [2] In addition to inducing apoptosis of Ba/F3 cells transformed with wild-type BCR-ABL with an IC50 of 5.2 μM, 17-AAG has the ability to induce apoptosis of cells transformed with imatinib mesylate-resistant T315I and E255K BCR-ABL mutants with IC50 values of 2.3 μM and 1.0 μM, respectively, by inducing the degradation of both wild-type BCR-ABL protein and mutants. [3]
In vivo試験 17-AAG displays significantly higher binding affinity for Hsp90 from 3T3-src, B16 or CT26 xenografts in nude mice with IC50 values of 8-35 nM as compared with that from the normal tissues with IC50 values of 200-600 nM. [1] Administration of 17-AAG (~50 mg/kg) causes significant decline in AR, HER2, HER3, and Akt expression in a dose-dependent manner with >50% decline at dose of 50 mg/kg, resulting in the dose-dependent inhibition of androgen-dependent (CWR22) and -independent (CWR22R and CWRSA6) prostate cancer xenografts growth by 67%, 80% and 68% at dose of 50 mg/kg, respectively. [2]
臨床試験 A Phase II study of 17-AAG in patients with relapsed/refractory CD30 plus anaplastic large cell lymphoma (ALCL) relapsed/refractory mantle cell lymphoma (MCL) and relapsed/refractory classical Hodgkin's lymphoma (HL) has been completed.
特集 Displays very low toxicity toward normal cells.

プロトコル (参考用のみ)

キナーゼアッセイ: [1]

Hsp90 binding assays Purified native Hsp90 protein or cell lysates from HER-2-overexpressing cancer cells (BT474, N87, SKOV3 and SKBR3) or BT474 breast carcinoma cells in lysis buffer (20 mM HEPES, pH 7.3, 1 mM EDTA, 5 mM MgCl2, 100 mM KCl) are incubated with various concentrations of 17-AAG for 30 minutes at 4 °C, and then incubated with biotin-GM linked to BioMag streptavidin magnetic beads for 1 hour at 4 °C. Tubes are placed on a magnetic rack, and the unbound supernatant removed. The magnetic beads are washed three times in lysis buffer and heated for 5 minutes at 95 °C in SDS–PAGE sample buffer. Samples are analysed on SDS protein gels, and western blots done using indicated antibodies. Bands in the western blots are quantified using the Bio-rad Fluor-S MultiImager, and the percentage inhibition of binding of Hsp90 to the biotin-GM is calculated. The IC50 reported is the concentration of 17-AAG needed to cause half-maximal inhibition of binding.

細胞アッセイ: [1]

細胞株 BT474, SKBR3, N87, SKOV3, MCF7, MDA468, Hs578T, Hs578Bst, A549, HT29, U87, SKMG3, HT1080, RPTEC, NDF, HMVEC, HMEC, HUVEC, and PBMC cells
濃度 Dissolved in DMSO, final concentrations ~10 μM
反応時間 5 days
実験の流れ Cells are seeded in 96-well plates at 2,000 cells per well in a final culture volume of 100 μL for 24 hours before the addition of increasing concentrations of 17-AAG that is incubated for 5 days. Viable cell number is determined using the Celltiter 96 AQueous Nonradioactive Cell Proliferation Assay. The value of the background absorbance at 490 nm (A490) of wells not containing cells is subtracted. Percentage of viable cells = (A490 of 17-AAG treated sample/A490 untreated cells) × 100. The IC50 is defined as the concentration that gave rise to 50% viable cell number.

動物実験: [2]

動物モデル Male nu/nu athymic mice inoculated s.c. with androgen-dependent CWR22 xenograft, and female nu/nu athymic mice inoculated s.c. with androgen-independent xenografts CWR22R and CWRSA6
製剤 Dissolved in DMSO, and diluted in egg phospholipids (EPL) vehicle
投薬量 ~50 mg/kg
投与方法 Injection i.p.

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

SpeciesMouseRatRabbitGuinea pigHamsterDogMonkeyBaboon
Weight (kg)0.020.151.80.40.0810312
Body Surface Area (m2)0.0070.0250.150.050.020.50.240.6
Km factor361285201220
Animal A (mg/kg) = Animal B (mg/kg) multiplied by  Animal B Km
Animal A Km

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×  mouse Km(3)  = 11.2 mg/kg
rat Km(6)
1

参考

化学情報

Download 17-AAG (Tanespimycin) SDF
分子量 585.69
化学式

C31H43N3O8

CAS No. 75747-14-7
保管 2年-20℃
6月-80℃in solvent
別名 CP127374,NSC-330507, KOS 953
溶解度 (25°C) * In vitro DMSO 117 mg/mL (199.76 mM)
エタノール 5 mg/mL (8.53 mM)
<1 mg/mL (<1 mM)
In vivo
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
化学名 17-demethoxy-17-(2-propenylamino)- [(3R,5R,6S,7R,8E,10R,11R,12Z,14E)-6-Hydroxy-5,11,21-trimethoxy-3,7,9,15-tetramethyl-16,20,22-trioxo-17-azabicyclo[16.3.1]docosa-1(21),8,12,14,18-pentaen-10-yl] carbamate

カスタマーフィードバック (6)


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Rating
Source PNAS, 2011, 108, 7535-40. 17-AAG (Tanespimycin) purchased from Selleck
Method Western blot
Cell Lines H3122 CR cells
Concentrations 10 nM
Incubation Time 72 h
Results As shown in Fig. A, 17-AAG potently suppressed cell growth in both parental H3122 and H3122 CR cells.However, in contrast to NVP-TAE684 and AP26113, 17-AAG also inhibited the viability of SKBR3 and BT474 cell lines, both of which harbor HER2 amplification and are known to be sensitive to Hsp90 inhibition (26, 27). 17-AAG treatment decreased both p-ALK level and ALK protein expression with similar potencies in the parental and resistant cells (Fig. B).

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Rating
Source Oncotarget, 2014, 5, 4269-82. 17-AAG (Tanespimycin) purchased from Selleck
Method Western blot
Cell Lines Ls-174T, HCT116, Caco2, Hke3 cells
Concentrations 0.5, 2 uM
Incubation Time 24 h
Results Colon cancer cells harboring WT or MT K-Ras were treated with 17-AAG and effects on the Ras expression were analyzed by WB. Results in Figure showed that incubation with 17-AAG only down-regulates K-Ras in K-Ras MT cells but decreases Raf-1 {an established Hsp90 client} in all cell lines. The result, for the first time, demonstrated that both transfected and endogenous MT K-Ras is an Hsp90 client protein.

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Rating
Source Mol Cell Biol, 2013, 33(12), 2375-87. 17-AAG (Tanespimycin) purchased from Selleck
Method Western blot
Cell Lines NIH 3T3 cells
Concentrations 25, 50 uM
Incubation Time 4 h
Results 17-AAG and SNX-2112, both of which induce the UPR by targeting the chaperone HSP90, decreased mSmoM2 protein levels (lanes 2 to 5 compared to lane 1), further supporting the sensitivity of active Smo mutants to UPR induction.

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Rating
Source J Biol Chem, 2012, 287, 44109-20. 17-AAG (Tanespimycin) purchased from Selleck
Method Western Blot
Cell Lines Dopaminergic Neuronal Cell lines
Concentrations 10-20uM
Incubation Time
Results As expected, both complex IV activity and Hsp60 levels exhibited a dose-dependent decrease in response to treatment with 17-AAG (Fig. 4A). However, 17-AAG treatment did not alter levels of Hsp90 and LRPPRC levels

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Rating
Source Mol Cancer, 2014, 13, 150. 17-AAG (Tanespimycin) purchased from Selleck
Method Western blot
Cell Lines SKBR3 cells
Concentrations 1, 2 uM
Incubation Time 24 h
Results Hsp90 and Cdc37 protein levels showed no distinct change according to a drug concentration gradient, whereas Hsp70, a marker of Hsp90 inhibition, the protein level was greatly induced by treatment with 17AAG or FW-04-806.

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Rating
Source Age, 2013, 35, 549-62. 17-AAG (Tanespimycin) purchased from Selleck
Method Western Blot
Cell Lines HFSN1 cells
Concentrations 0.1/0.5uM
Incubation Time 24 h
Results Figure 2c shows that the decrease in the level of Hsp90 after treatment with 0.5 μM of 17-AAG was accompanied by a decrease in the level of both the survivin and phospho-survivin proteins.

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description
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