Geldanamycin 化学構造
分子量: 560.64

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Quality Control & MSDS

製品説明

  • Compare HSP (e.g. HSP90) Inhibitors
    HSP (e.g. HSP90)製品生物活性の比較
  • 研究分野
  • Geldanamycinのメカニズム

製品の説明

生物活性

製品説明 ノーカット二量体Hsp90またはN末端領域Hsp90と結合している間、Geldanamycinは1.2のμMまたは0.78のμMによるKdによる天然既存のHsp90阻害剤です。
ターゲット

HSP90

HSP90 (N-terminal domain)

p185

IC50

1.2 μM (Kd)

0.78 μM (Kd) [1]

70 nM [4]

In vitro試験 Geldanamycin binds in the ATP-binding site in the N-terminus domain of Hsp90s (residues 1-220). Geldanamycin inhibits the ATPase activity of Hsp90 in a dose-dependent manner. [1] Geldanamycin causes a dose-dependent G2 arrest and reversible inhibiton o f entry into the S phase in A2780 human ovarian cell line. This inhibition is accompanied by p53 increase and finally demonstrated to be p53 dependent. [2] Geldanamycin causes polyubiquitination and proteasomal degradation of the p185 receptor protein-tyrosin kinase and shows a IC50 with 70 nM. [3, 4] Geldanamycin is a typical anti-tumor reagent, shows a mean GI50 with 0.18 μM against the panel of 60 human tumor cell lines. [5]
In vivo試験 Geldanamycin (50 mg//kg) shows 30% inhibition on pl85-associated phosphotyrosine levels in FRE/erbB-2 mice. [6]
臨床試験
特集

プロトコル (参考用のみ)

キナーゼアッセイ:

[1]

Isothermal Titration Calorimetry (ITC) of Nucelotide Binding The titration experiments are performed using the MSC system. In each experiment, 16 aliquots of 15 μL of geldanamycin (300 μM in 1% DMSO) are injected into 1.3 mL of protein (31 μM in 20 mMTris-HCl, pH 7.5, 1 mMEDTA) at 25 °C, and the resulting data are fit after subtracting the heats of dilution. Heats of dilution are determined in separate experiments from addition of geldanamycin into buffer and buffer into protein. No evidence for binding of DMSO in the nucleotide binding site is observed. Titration data are fit using a nonlinear least-squares curve-fitting algorithm with three floating variables: stoichiometry, binding constant (Kb) 1/Kd), and change of enthalpy of interaction (ΔH°). Dissociation constants estimated for geldanamycin binding to intact yeast Hsp90 is 1.22 μM, and for binding to Hsp90 N-terminal domain is 0.78 μM. No meaningful heat is observed with binding to the C-terminal fragment.
ATPase Assay The ATPase assay is based on a regenerating coupled enzyme assay in which the phosphorylation of ADP by pyruvate kinase at the expense of phosphoenolpyruvate is coupled to the reduction of the resulting pyruvate by lactate dehydrogenase at the expense of NADH.

細胞アッセイ:

[2]

細胞株 A2780 human ovarian cell line
濃度 0.001-10 μM
反応時間 3 hours
実験の流れ

Exponentially growing cells are treated with Geldanamycin and at various times DNA synthesis is assessed by incorporation of bromodeoxyuridine (BrdUrd) and flow cytometric analysis. No marked difference in total cell number is noted during this time course for treated and untreated cultures. BrdUrd (10 μM) is incorporated over a 4-h incubation period at 37 °C and cells are harvested and fixed in 70% ethanol. After denaturation of the DNA with 2 N HC1, cells are incubated with an anti-BrdUrd mouse monoclonal antibody followed by a fluorescein isothiocyanate (FITC)-linked goat anti-mouse IgG. Cells are stained for 30 minutes at room temperature with propidium iodide and analysed by flow cytometry using a Coulter EPICS Profile Analyzer.

動物実験:

[6]

動物モデル FRE/erbB-2 tumors in nu/nu mice
製剤 Geldanamycin is dissolved in DMSO.
投薬量 50 mg/kg
投与方法 Administered via 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 Geldanamycin SDF
分子量 560.64
化学式

C29H40N2O9

CAS No. 30562-34-6
保管 2年-20℃
6月-80℃in solvent
別名 NSC 122750
溶解度 (25°C) * In vitro DMSO 50 mg/mL warmed (89.18 mM)
<1 mg/mL (<1 mM)
エタノール <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 2-Azabicyclo[16.3.1]docosa-4,6,10,18,21-pentaene-3,20,22-trione, 9,13-dihydroxy-8,14,19-trimethoxy-4,10,12,16-tetramethyl-, 9-carbamate

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Source , , Antimicrob Agents Chemother, 2015, 10.1128/AAC.00946-15. Geldanamycin purchased from Selleck
Method Susceptibility Testing
Cell Lines
Concentrations 4 µg/Ml
Incubation Time 5 d
Results Mutation of the Hsp70 EELD motif in the stiA deletion background resulted in a similar near complete abolition of the heat and caspofungin stress responses compared to the Hsp70-AALA mutation alone, and had an additive effect on geldanamycin susceptibility.

文献中の引用 (4)

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
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