AT13387

 

Distributor Tel: +886-2-2827-1197jimmy@new.abscience.com.tw

Biological Activity

Description	AT13387 is a selective potent Hsp90 inhibitor with IC50 of 18 nM in A375 cells, displays a long duration of anti-tumor activity.
Targets	Hsp90
IC50	18 nM [1]
In vitro	The Kd for AT13387 binding is 0.7 nM. This compares to a Kd of 6.7 nM for the binding of the ansamycin 17-AAG to the same site. The mean stoichio metry of binding for AT13387 is 1.03. The inhibition of a number of isolated kinases by AT13387 is also investigated including CDK 1, CDK 2, CDK4, FGFR3, PKB-b, JAK2, VEGFR2, PDGFRβ and Aurora B. None of the tested kinases are significantly inhibited at concentrations below 30 μM. AT13387 is a potent inhibitor of the proliferat ion and survival of many different cell lines (such as MES-SA cell line) from a variety of different tumor types. Across a panel of 30 tumor cell lines, AT13387 potently inhibits cell proliferation with GI50 values in the range 13-260 nM. AT13387 inhibits proliferation of the non-tumorigenic human prostate epithelial cell line PNT2 with a GI50 value of 480 nM. [2]
In vivo	When given on an intermittent basis, AT13387 could be tolerated at doses of up to 70 mg/kg twice weekly or 90 mg/kg once weekly. Body weight loss in mice does not exceed 20% before recovering in all cases except one, and loss is highest following the second dose. Tumor growth inhibition is similar in NCI-H1975 for both dosing regimens. The maintenance of antitumor effects with such a prolonged off-treatment period is consistent with the extended pharmacodynamic action of AT13387 observed for mutant EGFR and other biomarkers in vitro and in vivo and the extended retention of AT13387 in tumors. [2]
Features

Protocol(Only for Reference)

Kinase Assay: ^[2]

HSP90 competition isothermal calorimetry	Kd values for AT13387 binding to HSP90 are determined with a competition Isothermal Calorimetry (ITC) format. ITC experiments are performed on a Micro Cal VP-ITC at 25 °C in a buffer comprising 25 mM Tris, 100 mM NaCl, 1 mM MgCl2 and 1 mM Tris(2-carboxy- ethyl)phosphine at pH 7.4 in order to maintain the higher affinit

Cell Assay: ^[2]

Cell lines	A375, 22RV1 and T474 cells
Concentrations	1 μM
Incubation Time	4 hours
Method	The human cell lines including A375, 22RV1, T474, DU1 45, LNCa P, MCF-7, DA-MB-468 are seeded into 96-well plates before the addition of AT13387 in 0.1% (v/v) DMSO. GI50 are determined using a 10-point dose response curve for three cell doubling times. After AT13387 incubation 10% (v/v), Alamar blueis added, and cells are incubated for a further 4 hours. Fluorescence is read.

Animal Study: ^[2]

Animal Models	Athymic BALB /c mice
Dosages	80 mg/kg
Administration	Intraperitoneal adminis tration
Solubility	15% Captisol, 30 mg/mL

1

References

Clinical Trial Information( data from http://clinicaltrials.gov)

NCT Number	Recruitment	Conditions	Sponsor /Collaborators	Start Date	Phases
NCT00878423	Active, not recruiting	Metastatic Solid Tumors	Astex Pharmaceuticals	2008-05	Phase 1
NCT01245218	Recruiting	Unspecified Adult Solid Tumor, Protocol Specific	National Cancer Institute (NCI)	2010-11	Phase 1
NCT01294202	Active, not recruiting	Gastrointestinal Stromal Tumor (GIST)	Astex Pharmaceuticals	2011-03	Phase 2
NCT01685268	Recruiting	Prostate Cancer	Astex Pharmaceuticals	2012-09	Phase 1|Phase 2
NCT01712217	Recruiting	Non-small Cell Lung Cancer(NSCLC)	Astex Pharmaceuticals	2012-10	Phase 1|Phase 2

Chemical Information

Download AT13387 SDF

Chemical Name	(2,4-dihydroxy-5-isopropylphenyl)(5-((4-methylpiperazin-1-yl)methyl)isoindolin-2-yl)methanone

Preparing Stock Solutions

Stock Solution (1ml DMSO)	1mM	10mM	20mM	30mM
Mass(mg)	0.40952	4.0952	8.1904	12.2856

Customer Reviews (1)

Click to enlarge	Rating
	Source	PLoS One. 2013;8(4):e59315 . AT13387 purchased from Selleck
	Method	ADP fluorescence assay
	Cell Lines	MCF-7 cells
	Concentrations
	Incubation Time	48 h
	Results	IC50 determinations of compound S1 and S13 on heat shock poteins ATPase activity using ADP fluorescence assay. (A) inhibition of HSP70 (B) inhibition of HSP90 The test compounds were diluted from mother plates (10 mM in 100% (v/v) DMSO) into series of concentration (in 2.0% (v/v) DMSO). AT13387 and 17-DMAG were used as positive controls in each assay. Data were performed in triplicate and analyzed by GraphPad.Prism.

Product Citations (1)

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  Identification, design and bio-evaluation of novel Hsp90 inhibitors by ligand-based virtual screening. [Jia J, et al. PLoS One 2013;8(4):e59315]