Zelavespib (PU-H71)

Catalog No.S8039 Synonyms: NSC 750424

For research use only.

Zelavespib (PU-H71, NSC 750424) is a potent and selective inhibitor of HSP90 with IC50 of 51 nM. Phase 1.

Zelavespib (PU-H71) Chemical Structure

CAS No. 873436-91-0

Selleck's Zelavespib (PU-H71) has been cited by 8 Publications

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Biological Activity

Description Zelavespib (PU-H71, NSC 750424) is a potent and selective inhibitor of HSP90 with IC50 of 51 nM. Phase 1.
Features Purine-based, HSP90-selective inhibitor.
Targets
HSP90 [1]
51 nM
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]

Cell Data
Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
MDA-MB-468 cells M1fMNmZ2dmO2aX;uJIF{e2G7 NGLne29KdmirYnn0c5J6KGGldHn2bZR6KGGpYXnud5QhUHOyOUCgbY4hcHWvYX6gZpJm[XO2IHPhcoNmeiCPRFGtUWIuPDZ6IHPlcIwhdGmwZTygSWM2OD1yLkCxNFIh|ryP MYKxOlM6Ojh{Mx?=
SKBr3 cells NYXhW4J2T3Kxd4ToJIlvcGmkaYTpc44h[XO|YYm= NGjmR4RIem:5dHigbY5pcWKrdHnvckBqdiCqdX3hckBjemWjc4SgZ4Fv[2W{IGPLRpI{KGOnbHygcIlv\SC3c3nu[{BUWkJuIFnDOVA:OC5yNTFOwG0> M4TISVE3Ozl{OEKz
MCF7 cells NFP3dW9HfW6ldHnvckBie3OjeR?= Ml7ENlQhcA>? M13pNGlvcGmkaYTpc44hd2ZiSIPwPVAhcW5iaIXtZY4hVUOINzDj[YxteyCjc4Pld5Nm\CCjczDI[ZIzKGyndnXsJIFnfGW{IEK0JIhzeyCkeTDX[ZN1\XKwIHLsc5QtKEmFNUC9NE4xPiEQvF2= M1vNPFE5PTdzOUK5
MRC5 cells NInScoVEgXSxdH;4bYNqfHliYYPzZZk> MX\DfZRwfG:6aXPpeJkh[WejaX7zeEBvd3KvYXygcJVv\yCoaXLyc4Jt[XO2IF3SR|Uh[2WubDDsbY5mNCCLQ{WwQVEh|ryP MnXWNVY{QTJ6MkO=
NCI-H1299 cells NXjyNZk{TnWwY4Tpc44h[XO|YYm= MoG2NVIhcA>? NGn3T4ZT\WS3Y4Tpc44hcW5ib4j5[4VvKGOxboP1cZB1cW:wIILheIUhcW5iaIXtZY4hVkOLLVixNlk6KGOnbHzzJIlv[3WkYYTl[EBnd3JiMUKgbJJ{ MorRNlU{QDN7MUW=
NCI-H69 cells Mke2SpVv[3Srb36gZZN{[Xl? NV7vbpFjOjRiaB?= NGDxSIpDcW6maX7nJIFn\mmwaYT5JJRwKEiVUEmwJIlvKGi3bXHuJG5EUS2KNkmgZ4VtdHNiYX\0[ZIhOjRiaILzJIJ6KG[udX;y[ZNk\W6lZTDwc4xiemm8YYTpc44h[XO|YYm= NGPLZnMyPzZyM{W0NC=>
NCI-N417 cells M3\UVWZ2dmO2aX;uJIF{e2G7 MmC1NlQhcA>? M4XUdmJqdmSrbnegZYZncW6rdImgeI8hUFOSOUCgbY4hcHWvYX6gUmNKNU52MUegZ4VtdHNiYX\0[ZIhOjRiaILzJIJ6KG[udX;y[ZNk\W6lZTDwc4xiemm8YYTpc44h[XO|YYm= MnzzNVc3ODN3NEC=
NCI-H187 cells MnXuSpVv[3Srb36gZZN{[Xl? M1\GcVI1KGh? M2DHRmJqdmSrbnegZYZncW6rdImgeI8hUFOSOUCgbY4hcHWvYX6gUmNKNUhzOEegZ4VtdHNiYX\0[ZIhOjRiaILzJIJ6KG[udX;y[ZNk\W6lZTDwc4xiemm8YYTpc44h[XO|YYm= NYq0XlVYOTd4MEO1OFA>
NCI-H510 cells NF7E[Y1HfW6ldHnvckBie3OjeR?= NEXM[FgzPCCq MnLFRolv\GmwZzDh[oZqdmm2eTD0c{BJW1B7MDDpckBpfW2jbjDOR2kuUDVzMDDj[YxteyCjZoTldkAzPCCqcoOgZpkh\my3b4Lld4NmdmOnIIDvcIFzcXqjdHnvckBie3OjeR?= MlSxNVc3ODN3NEC=
SKBR3 cells NYPYdo1FTnWwY4Tpc44h[XO|YYm= NH\oT24zPCCq M2n0dmJqdmSrbnegZYZncW6rdImgeI8hUFOSOUCgbY4hcHWvYX6gV2tDWjNiY3XscJMh[W[2ZYKgNlQhcHK|IHL5JIZtfW:{ZYPj[Y5k\SCyb3zhdol7[XSrb36gZZN{[Xl? MkPHNVc3ODN3NEC=
NCI-H526 cells M1HueWZ2dmO2aX;uJIF{e2G7 NVPwZ3ZLOSEQvF2= NUfWOVZMOjRiaB?= M3XJNmJqdmSrbnegZYZncW6rdImgeI8hUFOSOUCgbY4hcHWvYX6gUmNKNUh3Mk[gZ4VtdHNiYYSgNUB2VSCjZoTldkAzPCCqcoOgZpkh\my3b4Lld4NmdmOnIIDvcIFzcXqjdHnvckBie3OjeR?= MoTZNVc3ODN3NEC=
H69AR cells M3\RTWZ2dmO2aX;uJIF{e2G7 Ml2yPVYhcA>? NGCyeJZKdmirYnn0bY9vKG:oIFjTVFkxNW2nZHnheIVlKGGwdHnhdI9xfG:2aXOgZYN1cX[rdImgbY4hcHWvYX6gTFY6SVJiY3XscJMh[XO|ZYPz[YQh[XNiaX7keYN1cW:wIH;mJINmdGxiZ4Lve5RpKGG{cnXzeEBifCBzMDDh[pRmeiB7NjDodpMh[nlicILvdIllcXWvIHnv[Ill\SC|dHHpcolv\y2kYYPl[EBndG:5IHP5eI9u\XS{eR?= M3;wd|E4PjB|NUSw
NCI-H526 cells NEXOVmNHfW6ldHnvckBie3OjeR?= M4PqdFI1KGh? M3\5NWJqdmSrbnegZYZncW6rdImgeI8hUFOSOUCgbY4hcHWvYX6gUmNKNUh3Mk[gZ4VtdHNiYX\0[ZIhOjRiaILzJIJ6KG[udX;y[ZNk\W6lZTDwc4xiemm8YYTpc44h[XO|YYm= MUOxO|YxOzV2MB?=
Assay
Methods Test Index 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 19416831 28114285
Growth inhibition assay Cell viability 19416831
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 (from reference)

Kinase Assay:

[1]

  • 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.

Cell Research:

[1]

  • Cell lines: Human triple-negative breast cancers cell line MDA-MB-231
  • Concentrations: ~5μM
  • Incubation Time: 3 days
  • Method:

    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 the 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.

Animal Research:

[1]

  • Animal Models: Human triple-negative breast cancers xenografts MDA-MB-231
  • Dosages: 75 mg/kg
  • Administration: i.p. on an alternate day schedule

Solubility (25°C)

In vitro

Chemical Information

Molecular Weight 512.37
Formula

C18 H21 I N6 O2 S

CAS No. 873436-91-0
Storage 3 years -20°C powder
2 years -80°C in solvent
Smiles CC(C)NCCCN1C2=NC=NC(=C2N=C1SC3=C(C=C4C(=C3)OCO4)I)N

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Method for preparing in vivo formulation: Take μL DMSO master liquid, next addμL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O, mix and clarify.

Method for preparing in vivo formulation: Take μL DMSO master liquid, next add μL Corn oil, mix and clarify.

Note: 1. Please make sure the liquid is clear before adding the next solvent.
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Molarity Calculator

Mass Concentration Volume Molecular Weight

Clinical Trial Information

NCT Number Recruitment Interventions Conditions Sponsor/Collaborators Start Date Phases
NCT03935555 Recruiting Drug: PU-H71 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 Drug: PU-H71|Drug: Ruxolitinib Myelofibrosis|Primary Myelofibrosis|Post-polycythemia Vera Myelofibrosis|Post-essential Thrombocythemia Myelofibrosis Samus Therapeutics Inc. May 24 2018 Phase 1
NCT01393509 Active not recruiting Drug: PU-H71 Metastatic Solid Tumor|Lymphoma|Myeloproliferative Neoplasms (MPN) Memorial Sloan Kettering Cancer Center July 2011 Phase 1
NCT01581541 Terminated Drug: PU-H71 Solid Tumors|Lymphoma National Cancer Institute (NCI)|National Institutes of Health Clinical Center (CC) April 26 2011 Phase 1

(data from https://clinicaltrials.gov, updated on 2022-01-17)

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