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    Onalespib (AT13387)
    Onalespib (AT13387)

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    This product is for research use only, not for human use. We do not sell to patients.
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    InvivoChem Cat #: V0878
    CAS #: 912999-49-6 Purity ≥98%

    Description: Onalespib (formerly AT13387; AT-13387; AT 13387) is a novel, orally bioavailable, long-acting and isoindole-based small-molecule HSP90 (heat shock protein 90) inhibitor with potential antitumor activity. It inhibits HSP90 with an IC50 of 18 nM in A375 cells, displays a long duration of anti-tumor activity. Onalespib is being studies in clinical trials for men with CRPC, in particular thos who have failed treatment with abiraterone acetate

    References: Cancer Sci. 2012 Mar;103(3):522-7.

    Related CAS: 1019889-35-0 (lactate); 912999-49-6 (free base);

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    Molecular Weight (MW)409.52
    FormulaC24H31N3O3
    CAS No.912999-49-6(free base);
    Storage-20℃ for 3 years in powder form
    -80℃ for 2 years in solvent
    Solubility (In vitro)DMSO: 25 mg/mL (61.0 mM)
    Water: <1 mg/mL
    Ethanol: <1 mg/mL
    Solubility (In vivo)2% DMSO+30% PEG 300+ddH2O: 10 mg/mL
    SynonymsOnalespib lactate; AT13387; AT-13387; AT 13387; Onalespib; 

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

    SMILES Code: O=C(C1=CC(C(C)C)=C(O)C=C1O)N2CC3=C(C=C(CN4CCN(C)CC4)C=C3)C2


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    In Vitro

    In vitro activity: 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.


    Kinase Assay: 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 affinity.


    Cell Assay: 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.

    In VivoWhen 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.
    Animal modelAthymic BALB /c mice
    Formulation & DosageDissolved in 17.5% cyclodextrin; 80 mg/kg; i.p. injection
    References

    Cancer Sci. 2012 Mar;103(3):522-7.


    These protocols are for reference only. InvivoChem does not independently validate these methods.

    Effects of AT13387 treatment on HSP90 client protein levels. Cancer Sci. 2012 Mar;103(3):522-7. 



    Onalespib (AT13387)
    Pharmacokinetic analyses of AT13387.
     
    Onalespib (AT13387)
    AT13387 has a long duration of inhibition in vitro.



    Onalespib (AT13387)
    AT13387 is efficacious in multiple xenograft models on a once a week dosing schedule. Cancer Sci. 2012 Mar;103(3):522-7. 
     
    Onalespib (AT13387)
    AT13387 in vivo duration of action. Cancer Sci. 2012 Mar;103(3):522-7. 


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