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Zelavespib (PU-H71)
別名：NSC 750424
Zelavespib (PU-H71, NSC 750424) is a potent and selective inhibitor of HSP90 with IC50 of 51 nM. Phase 1.
CAS No. 873436-91-0
文献中Selleckの製品使用例（18）
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製品安全説明書
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純度：
99.01%
99.01
Zelavespib (PU-H71)関連製品
シグナル伝達経路
HSP (HSP90)阻害剤の選択性比較
Cell Data
| Cell Lines | Assay Type | Concentration | Incubation Time | 活性情報 | PMID |
|---|---|---|---|---|---|
| NCI-H526 cells | Function assay | 1 μM | 24 h | Binding affinity to HSP90 in human NCI-H526 cells at 1 uM after 24 hrs by fluorescence polarization assay | |
| MCF7 cells | Function assay | 24 h | Inhibition of Hsp90 in human MCF7 cells assessed as Her2 level after 24 hrs by Western blot, IC50=0.06 μM | ||
| NCI-H1299 cells | Function assay | 12 h | Reduction in oxygen consumption rate in human NCI-H1299 cells incubated for 12 hrs | ||
| NCI-H69 cells | Function assay | 24 h | Binding affinity to HSP90 in human NCI-H69 cells after 24 hrs by fluorescence polarization assay | ||
| NCI-N417 cells | Function assay | 24 h | Binding affinity to HSP90 in human NCI-N417 cells after 24 hrs by fluorescence polarization assay | ||
| NCI-H187 cells | Function assay | 24 h | Binding affinity to HSP90 in human NCI-H187 cells after 24 hrs by fluorescence polarization assay | ||
| NCI-H510 cells | Function assay | 24 h | Binding affinity to HSP90 in human NCI-H510 cells after 24 hrs by fluorescence polarization assay | ||
| SKBR3 cells | Function assay | 24 h | Binding affinity to HSP90 in human SKBR3 cells after 24 hrs by fluorescence polarization assay | ||
| H69AR cells | Function assay | 96 h | Inhibition of HSP90-mediated antiapoptotic activity in human H69AR cells assessed as induction of cell growth arrest at 10 after 96 hrs by propidium iodide staining-based flow cytometry | ||
| NCI-H526 cells | Function assay | 24 h | Binding affinity to HSP90 in human NCI-H526 cells after 24 hrs by fluorescence polarization assay | ||
| MDA-MB-468 cells | Function assay | Inhibitory activity against Hsp90 in human breast cancer MDA-MB-468 cell line, EC50=0.0102 μM | |||
| SKBr3 cells | Growth inhibition assay | Growth inhibition in human breast cancer SKBr3 cell line using SRB, IC50=0.05 μM | |||
| MRC5 cells | Cytotoxicity assay | Cytotoxicity against normal lung fibroblast MRC5 cell line, IC50=1 μM | |||
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生物活性
| 製品説明 | Zelavespib (PU-H71, NSC 750424) is a potent and selective inhibitor of HSP90 with IC50 of 51 nM. Phase 1. | ||
|---|---|---|---|
| 特性 | Purine-based, HSP90-selective inhibitor. | ||
| Targets |
|
| In Vitro | ||||
| In vitro | Zelavespib (PU-H71) (1 μM) potently suppresses the growth of triple-negative breast cancers (TNBC) cell lines MDA-MB-468, MDA-MB-231, and HCC-1806 with IC50 of 65, 140 and 87 nM, respectively. This compound (1 μM) kills 80%, 65%, and 80% of the initial population of MDA-MB-468, MDA-MB-231, and HCC-1806 cells, respectively. It (0.25-1 μM) induces a dose-dependent degradation or inactivation of tumor driving molecules, including EGFR, IGF1R, HER3, c-Kit, Raf-1and Akt. Treatment for 24 h with 1 μM PU-H71, augments the percent of cells in G2-M phase of MDA-MB-468 to 69%, mediated by reduction in CDK1 and Chk1 expression. It induces apoptosis in TNBC in part by inactivation and downregulation of Akt and Bcl-xL. It leads to a proteasome-mediated reduction in IRAK-1 and TBK1 levels, resulting in approximately 84% and 90% reduction in NF-κB activity in MDA-MB-231 cells treated with 0.5 and 1 μM PU-H71, respectively. It markedly contains MDA-MB-231 cell invasion, with 90% suppression at 1 μM. [1] At 2.5 μM, it generates endoplasmic reticulum (ER) stress and activated the Unfolded Protein Response (UPR) as evidenced by XBP1 mRNA splicing (2.3-fold) and up-regulation of Grp94 (3.7-fold), Grp78 (4.9-fold), and CHOP (48-fold) protein expression and ATF4 (1.8-fold) mRNA expression. At 1 μM, it induces the mitochondrial pathway of apoptosis in HeLa cells, mediated by caspase but not calpain activation. In response to PU-H71-induced ER stress, apoptosis is triggered in melanoma, cervix, colon, liver and lung cancer cells, but not in normal human fibroblasts. It is able to induce apoptosis overcoming the resistance conferred by Bcl-2. [2] At 30 nM, it significantly reduces NOS2 activity (60% reduction) and expression in LI (1 μg/mL LPS and 5 ng/mL IFN γ)-stimulated astrocytes via inhibiting NF-κB element activation. It displays similar effects on microglial cells as on astrocytes, with 50 nM PU-H71 needed to significantly reduce the LPS dependent nitrite release. [3] | |||
|---|---|---|---|---|
| Kinase Assay | HSP90 binding assay | |||
| Measurements are performed in black 96-well microtiter plates. Cell lysates are prepared by rupturing cellular membranes by freezing at -70℃ and dissolving the cellular extract in HFB [20 mM Hepes (K), pH 7.3, 50 mM KCl, 5 mM MgCl2, 20 mM Na2MoO4, 0.01% Nonidet P-40] with added protease and phosphatase inhibitors. Saturation curves are recorded in which fluorescently labeled geldanamycin (Cy3B-GM) (3 nM) is treated with increasing amounts of cellular lysates. The amount of lysate that results in polarization (mP) readings corresponding to 90%-99% bound ligand is chosen for the competition study. Here, each 96-well plate contains 3 nM Cy3B-GM, cellular lysate (amounts as determined and normalized to total Hsp90 as determined by Western blot analysis using Hsp90 purified from HeLa cells as standard) and Zelavespib (PU-H71) in a final volume of 100 μL. The plate is left for 24 h on a shaker at 4 ℃, and the fluorescence polarization (FP) values in mP are recorded. EC50 values are determined as the competitor concentrations at which 50% of the Cy3B-GM is displaced. FP measurements are performed on an Analyst GT microplate reader. | ||||
| 細胞実験 | 細胞株 | Human triple-negative breast cancers cell line MDA-MB-231 | ||
| 濃度 | ~5μM | |||
| 反応時間 | 3 days | |||
| 実験の流れ | Exponentially growing MDA-MB-231 cells are seeded into black 96-well microtiter plates and incubated in medium containing either vehicle control (DMSO) or compounds for the indicated time at 37 ℃. Plates containing 3 replicate wells per assay condition are seeded at a density of 8×103 cells for each cell line in 100μL medium. After exposure of cells to Zelavespib (PU-H71) or other Hsp90 inhibitors, plates are equilibrated to room temperature (20-25 ℃) for approximately 30 min, and 100 μL CellTiter-Glo reagent are added to each well. Plates are mixed for 2 min on an orbital shaker and then incubated for 15 min to 2 h at room temperature. The luminescence signal in each well is measured in an Analyst GT microplate reader. |
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| 実験結果図 | Methods | Biomarkers | 結果図 | PMID |
| Western blot | AKT / c-Myc / pERK / RAF1 / EWS-FLI1 / IGF-1R / PDGFRA / c-KIT / SRC EGFR / HER3 / IGF-1R / c-Kit / Raf-1 / Akt / p90RSK / CSK / Hsp70 / Hsp90 Bcl-xl / p-PDK1 / p-AKT / cPARP LYN / SYK / BTK / AKT / MEK / ERK |
|
24388362 | |
| Growth inhibition assay | Cell viability |
|
19416831 | |
| In Vivo | ||
| In Vivo | Zelavespib (PU-H71) administered at 75 mg/kg a.d. in the MDA-MB-231 model induces a 100% complete response, and tumors are reduced to scar tissue after 37 days of treatment, accompanied with reduction in many proliferative and anti-apoptotic molecules, namely an 80%, 95%, 99%, 80%, and 65% decrease in EGFR, HER3, Raf-1, Akt, and p-Akt, respectively. When administered at 75 mg/kg 3 times per week, this compound induces a 96% inhibition of tumor growth, accompanied by an 60% reduction in tumor cell proliferation, an 85% decline in activated Akt associated with survival and high invasive potential, and a 6-fold increase in apoptosis. [1] | |
|---|---|---|
| 動物実験 | 動物モデル | Human triple-negative breast cancers xenografts MDA-MB-231 |
| 投与量 | 75 mg/kg | |
| 投与経路 | i.p. on an alternate day schedule | |
| NCT Number | Recruitment | Conditions | Sponsor/Collaborators | Start Date | Phases |
|---|---|---|---|---|---|
| NCT05612633 | Withdrawn | Accelerated Phase MPN|Blast Phase MPN |
Samus Therapeutics Inc. |
June 15 2022 | Phase 2 |
| NCT03935555 | Terminated | Primary Myelofibrosis (PMF)|Post-Polycythemia Vera Myelofibrosis (Post-PV MF)|Post-Essential Thrombocythemia Myelofibrosis (Post-ET MF) |
Samus Therapeutics Inc. |
August 12 2019 | Phase 1 |
| NCT03373877 | Terminated | Myelofibrosis|Primary Myelofibrosis|Post-polycythemia Vera Myelofibrosis|Post-essential Thrombocythemia Myelofibrosis |
Samus Therapeutics Inc. |
May 24 2018 | Phase 1 |
| NCT01393509 | Completed | Metastatic Solid Tumor|Lymphoma|Myeloproliferative Neoplasms (MPN) |
Memorial Sloan Kettering Cancer Center |
July 6 2011 | Phase 1 |
| NCT01581541 | Terminated | Solid Tumors|Lymphoma |
National Cancer Institute (NCI)|National Institutes of Health Clinical Center (CC) |
April 26 2011 | Phase 1 |
|
化学情報
| 分子量 | 512.37 | 化学式 | C18 H21 I N6 O2 S |
| CAS No. | 873436-91-0 | SDF | -- |
| Smiles | CC(C)NCCCN1C2=NC=NC(=C2N=C1SC3=C(C=C4C(=C3)OCO4)I)N | ||
| 保管 | |||
|
In vitro |
DMSO : 100 mg/mL ( (195.17 mM)； 吸湿したDMSOは溶解度を減少させます。新しいDMSOをご使用ください。) Water : 100 mg/mL Ethanol : 100 mg/mL |
モル濃度計算器 |
|
in vivo Add solvents to the product individually and in order. |
投与溶液組成計算機 | |||||
実験計算
投与溶液組成計算機(クリア溶液)
ステップ１：実験データを入力してください。（実験操作によるロスを考慮し、動物数を1匹分多くして計算・調製することを推奨します）
mg/kg
g
μL
匹
ステップ２：投与溶媒の組成を入力してください。（ロット毎に適した溶解組成が異なる場合があります。詳細については弊社までお問い合わせください）
% DMSO
%
% Tween 80
% ddH2O
%DMSO
%
計算結果：
投与溶媒濃度： mg/ml;
DMSOストック溶液調製方法： mg 試薬を μL DMSOに溶解する（濃度 mg/mL, 注：濃度が当該ロットのDMSO溶解度を超える場合はご連絡ください。 )
投与溶媒調製方法：Take μL DMSOストック溶液に μL PEG300，を加え、完全溶解後μL Tween 80，を加えて完全溶解させた後 μL ddH2O，を加え完全に溶解させます。
投与溶媒調製方法：μL DMSOストック溶液に μL Corn oil，を加え、完全溶解。
注意：１.ストック溶液に沈殿、混濁などがないことをご確認ください；
２.順番通りに溶剤を加えてください。次のステップに進む前に溶液に沈殿、混濁などがないことを確認してから加えてください。ボルテックス、ソニケーション、水浴加熱など物理的な方法で溶解を早めることは可能です。
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