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    CCT245737
    CCT245737

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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 #: V2732
    CAS #: 1489389-18-5Purity ≥98%

    Description: CCT245737 is a novel, potent, orally available and selective ATP-competitive inhibitor of CHK1 (checkpoint kinase 1) with an IC50 of 30-220 nM. It shows<50% 10='' 121='' inhibition='' at='' m='' for='' representing='' a='' selectivity='' chk1='' of=''>5000-fold over these enzymes. CCT245737 enhanced gemcitabine antitumor activity to a greater degree than for higher doses of either agent alone, without increasing toxicity. CCT2457374 shows an increase in plasma and tumoconcentrations between 3-100 mg/kg. CCT245737 has low predicted doses and exposures in humans which mitigated the residual weak in vitro hERG inhibition. 

    References: Oncotarget. 2016 Jan 19;7(3):2329-42.

    Related CAS#:1489389-23-2 (S-enantiomer)

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    Molecular Weight (MW)379.34
    FormulaC16H16F3N7O
    CAS No.1489389-18-5
    Storage-20℃ for 3 years in powder form
    -80℃ for 2 years in solvent
    Solubility (In vitro)DMSO: 75 mg/mL (197.7 mM)
    Water: <1 mg/mL
    Ethanol: 9 mg/mL (23.7 mM)
    SMILES N#CC1=NC=C(NC2=NC=C(C(F)(F)F)C(NC[[email protected]]3CNCCO3)=C2)N=C1
    SynonymsCCT 245737; CCT245737; CCT-245737.


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    In Vitro

    In vitro activity: CCT245737 is a potent inhibitor of recombinant human CHK1 with IC50 of 1.4±0.3 nM (mean±SD, n = 3, EZ Reader II assay). There is > 1,000-fold selectivity for CHK1 versus the functionally important kinases CDK1 and CHK2 (IC50=1.26-2.44 and 9.03 μM, respectively), and at least a 90-fold selectivity against cross-reacting kinases such as ERK8, PKD1, RSK1 and 2. CCT245737 potently inhibits cellular CHK1 activity (IC50 30-220nM) and enhances gemcitabine and SN38 cytotoxicity in multiple human tumor cell lines and human tumor xenograft models. It can abrogate an etoposide-induced G2/M arrest. CCT245737 has high cell permeability, as measured by transport across a CaCo2 cell monolayer.


    Kinase Assay:  CCT245737 shows<50% 10='' 121='' inhibition='' at='' m='' for='' representing='' a='' selectivity='' chk1='' of=''>5000-fold over these enzymes. Commercial in vitro 33P radiometric kinase assays are carried out against 124 human kinases using 10 μM CCT245737 at ATP concentrations corresponding to the kinase Km, ATP. Other kinase IC50 determinations for CHK2 and FLT3 are performed using a commercial assay or in-house with recombinant human CHK1 on a LabChip® EZ Reader II or CDK1 in a DELFIA assay.


    Cell Assay: Cytotoxicity is determined as the drug concentration that gave 50% inhibition of tumor cell proliferation (GI50) using a 96h (i.e. 4-doublings) Sulforhodamine B (SRB) assay. Inhibition of intracellular CHK1 activity is measured using a cell based ELISA for the abrogation of an etoposide induced G2 checkpoint (mitosis induction assay, MIA).

    In VivoMouse oral bioavailability is complete (100%) with extensive tumor exposure. CCT245737 shows significant single-agent activity against a MYC-driven mouse model of B-cell lymphoma. An i.v. dose of 10mg/kg CCT245737 into BALB/c mice gives a peak plasma concentration of 4μmol/L, with a half-life of 2.86h, an AUC0-∞ of 9.96μmol.h/L, a plasma clearance of 2.1L/h/kg and a large volume of distribution (0.19L). The equivalent oral dose gave an almost identical profile with an AUC0-∞ of 10.4μmol.h/L showing complete oral bioavailability (F = 105%). In a word, CCT245737 shows complete oral bioavailability with linear pharmacokinetics and high tumor/plasma ratios consistent with extensive tumor exposure. Adequate CCT245737 tumor drug exposure takes a significant antitumor activity.
    Animal modelBALB/c mice
    Formulation & DosageDissolved in DPTW (10% DMSO, 20% PEG400, 5% Tween 80 and 65% water) for oral vehicle; 10mg/kg(i.v.); 150mg/kg(p.o.); i.v. or p.o.
    ReferencesOncotarget. 2016 Jan 19;7(3):2329-42.


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

    CCT245737

    Structure and cellular pharmacology of CCT245737. Oncotarget. 2016 Jan 19;7(3):2329-42. 
     

    CCT245737

    Summary of the pharmacokinetic and pharmacodynamic properties of CCT245737 in vivo. Oncotarget. 2016 Jan 19;7(3):2329-42. 
     

    CCT245737

    Therapeutic activity of CCT245737 in combination with gemcitabine or irinotecan in human tumor xenografts. Oncotarget. 2016 Jan 19;7(3):2329-42. 
     

    CCT245737

    Development and validation of a pharmacodynamic biomarker assay for CCT245737 activity in human lung tumor xenografts. Oncotarget. 2016 Jan 19;7(3):2329-42. 
     

    CCT245737

    Antitumor activity of single-agent CCT245737 in an Eμ-Myc mouse model of human B-cell lymphocytic leukemia. Oncotarget. 2016 Jan 19;7(3):2329-42. 


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