PU-H71
Catalog No.S8039 Synonyms: NSC 750424
Molecular Weight(MW): 512.37
PU-H71 is a potent and selective inhibitor of HSP90 with IC50 of 51 nM. Phase 1.
Cited by 2 Publications
1 Customer Review
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Effects of low-level HSP90 inhibition (by ganetespib, 2-5 nM; PU-H71, 40-70 nM) or febrile-range temperature (39 ℃) on HSP70 and HSP90 protein levels in FANCA wild-type cells. High-level HSP90 inhibition (ganetespib, 25 nM; PU-H71, 300 nM) as well as proteotoxic proteasomal inhibition (MG132, 2.5 mM) induced the expression of HSP70. Constitutive (upper band: C) and inducible forms (lower band: I) of HSP70 are indicated. HSP90 levels are shown for comparison.
Cell, 2017, 168(5):856-866. PU-H71 purchased from Selleck.
Purity & Quality Control
Choose Selective HSP (e.g. HSP90) Inhibitors
Biological Activity
| Description | PU-H71 is a potent and selective inhibitor of HSP90 with IC50 of 51 nM. Phase 1. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Features | Purine-based, HSP90-selective inhibitor. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| In vitro |
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. PU-H71 (1 μM) kills 80%, 65%, and 80% of the initial population of MDA-MB-468, MDA-MB-231, and HCC-1806 cells, respectively. PU-H71 (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. PU-H71 induces apoptosis in TNBC in part by inactivation and downregulation of Akt and Bcl-xL. PU-H71 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 1μM PU-H71, respectively. PU-H71 markedly contains MDA-MB-231 cell invasion, with 90% suppression at 1 μM. [1] PU-H71 (2.5 μM) 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. PU-H71 (1 μM) 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. PU-H71 is able to induce apoptosis overcoming the resistance conferred by Bcl-2. [2] PU-H71 (30 n M) 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. PU-H71 displays similar effects on microglial cells as on astrocytes, with 50 nM PU-H71 needed to significantly reduce the LPS dependent nitrite release. [3] |
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| Cell Data |
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| In vivo | 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. PU-H71 (75 mg/kg, 3 times per week) 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] |
Protocol
| Kinase Assay: |
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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 tested Hsp90 inhibitor 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. |
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Solubility (25°C)
| In vitro | DMSO | 100 mg/mL (195.17 mM) |
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| Ethanol | 100 mg/mL (195.17 mM) | |
| Water | 34 mg/mL warmed (66.35 mM) |
* 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.
Chemical Information
| Molecular Weight | 512.37 |
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| Formula | C18 H21 I N6 O2 S |
| CAS No. | 873436-91-0 |
| Storage | powder |
| in solvent | |
| Synonyms | NSC 750424 |
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Clinical Trial Information
| NCT Number | Recruitment | Conditions | Sponsor/Collaborators | Start Date | Phases |
|---|---|---|---|---|---|
| NCT03373877 | Recruiting | Myelofibrosis|Primary Myelofibrosis|Post-polycythemia Vera Myelofibrosis|Post-essential Thrombocythemia Myelofibrosis | Samus Therapeutics Inc. | May 24 2018 | Phase 1 |
| NCT03373877 | Recruiting | Myelofibrosis|Primary Myelofibrosis|Post-polycythemia Vera Myelofibrosis|Post-essential Thrombocythemia Myelofibrosis | Samus Therapeutics Inc. | May 24 2018 | Phase 1 |
| NCT03166085 | Active not recruiting | Metastatic Breast Cancer | Memorial Sloan Kettering Cancer Center|Samus Therapeutics Inc. | May 23 2017 | Phase 1 |
| NCT03166085 | Active not recruiting | Metastatic Breast Cancer | Memorial Sloan Kettering Cancer Center|Samus Therapeutics Inc. | May 23 2017 | Phase 1 |
| NCT01393509 | Active not recruiting | Metastatic Solid Tumor|Lymphoma|Myeloproliferative Neoplasms (MPN) | Memorial Sloan Kettering Cancer Center | July 2011 | Phase 1 |
| NCT01393509 | Active not recruiting | Metastatic Solid Tumor|Lymphoma|Myeloproliferative Neoplasms (MPN) | Memorial Sloan Kettering Cancer Center | July 2011 | Phase 1 |
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