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Zelavespib (PU-H71)

Name: Zelavespib (PU-H71)
Brand: Selleck Chemicals
SKU: S8039
Rating: 5 (8 reviews)

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.

CAS No. 873436-91-0

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

1 Customer Review

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HSP (HSP90) Signaling Pathway Map

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?=

Click to View More Cell Line Experimental Data

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

References

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
Storage	2 years	-80°C	in solvent
Smiles	CC(C)NCCCN1C2=NC=NC(=C2N=C1SC3=C(C=C4C(=C3)OCO4)I)N

In vivo Formulation Calculator (Clear solution)

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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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