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    Agerafenib (CEP-32496; RXDX-105; AC013773)
    Agerafenib (CEP-32496; RXDX-105; AC013773)

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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 #: V1013
    CAS #: 1188910-76-0Purity ≥98%

    Description: Agerafenib (formerly RXDX105; AC013773; RXDX-105; CEP-32496; AC-01377) is a potent and orally bioactive inhibitor of BRAFV600E and c-Raf with potential antitumor activity. It inhibits BRAFV600E with Kd values of 14 nM nM and 39 nM, respectively. Agerafenib showed little or no inhibition against other kinases such as MEK-1, MEK-2, ERK-1 and ERK-2. 

    References: J Med Chem, 2012, 55(3), 1082-1105.Mol Cancer Ther, 2012, 11(4), 930-941.

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    Molecular Weight (MW)517.46
    FormulaC24H22F3N5O5
    CAS No.1188910-76-0
    Storage-20℃ for 3 years in powder form
    -80℃ for 2 years in solvent
    Solubility (In vitro)DMSO: 9 mg/mL (17.4 mM)
    Water: <1 mg/mL
    Ethanol: <1 mg/mL
    Solubility (In vivo)15% Captisol: 15 mg/mL
    SynonymsAgerafenib; CEP32496; CEP 32496; RXDX 105; RXDX105; AC013773; RXDX-105; CEP-32496; AC 013773; AC-013773. 


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    In Vitro

    In vitro activity: CEP-32496 inhibits A375 cell (BRAFV600E) proliferation with EC50 of 78 nM. CEP-32496 exhibits more sensitive cytotoxicity for tumor cell lines (A375, SK-MEL-28, Colo-205, Colo-679, and HT-144) expressing mutant BRAF than those expressing wild-type BRAF (HCT116, Hs578T, LNCaP, DU145, and PC-3). CEP-32496 inhibits mitogen-activated protein (MAP)/extracellular signal-regulated (ER) kinase (MEK) phosphorylation (pMEK) in human melanoma (A375) and colorectal cancer (Colo-205) cell lines with IC50 of 78 nM and 60 nM, respectively.


    Kinase Assay: CEP-32496 inhibits A375 cell (BRAFV600E) proliferation with EC50 of 78 nM. CEP-32496 exhibits more sensitive cytotoxicity for tumor cell lines (A375, SK-MEL-28, Colo-205, Colo-679, and HT-144) expressing mutant BRAF than those expressing wild-type BRAF (HCT116, Hs578T, LNCaP, DU145, and PC-3). CEP-32496 inhibits mitogen-activated protein (MAP)/extracellular signal-regulated (ER) kinase (MEK) phosphorylation (pMEK) in human melanoma (A375) and colorectal cancer (Colo-205) cell lines with IC50 of 78 nM and 60 nM, respectively. 


    Cell Assay: A375 Cells are seeded at 104 cells per well in DMEM with 10% fetal calf serum and allowed to attach. The cells are washed with PBS and switched to DMEM with 0.5% of serum and incubated overnight. CEP-32496 is then added at various concentrations with a final DMSO concentration of 0.5% and incubated for 72 h. At the end of incubation, a Cell Titer Blue is added per instructions, and incubation is continued for 3 hours. Remaining viable cells are quantified by measuring the strength of the fluorescence signal using SoftMax Pro (excitation at 560 nm and emission at 590 nm). IC50 values are derived using a 9-point curve fitted with Igor Pro and are presented as mean values from experiments performed in duplicate. Variability between individual values is less than 2-fold.

    In VivoCEP-32496 exhibits good stability in mouse, dog, monkey, and human liver microsomal preparations with measured intrinsic clearance values of<23 2='' mg='' and=''>60 min in all assays. CEP-32496 (30 mg/kg, orally, BID) exhibits tumor stasis and a 40% incidence of partial tumor regressions (PRs) in Colo-205 xenograft mouse model, whereas the 100 mg/kg dose group exhibits both tumor stasis and an 80% incidence of PRs. CEP-32496 (30 mg/kg, orally, BID) leads to a 50% and 75% inhibition of normalized pMEK in tumor lysates at the 2 hours and 6 hours postdose time point, respectively, while a 55 mg/kg dose results in a 75% to 57% inhibition of pMEK at 2 hours through 10 hours post administration in Colo-205 xenograft mouse model. CEP-32496 is orally bioavailable in multiple preclinical species (>95% in rats, dogs, and monkeys). CEP-32496 (100 mg/kg) results in inhibition of pMEK and pERK and sustained tumor stasis and regressions in BRAF(V600E) colon carcinoma xenografts in nude mice.
    Animal modelColo-205 xenograft mouse model
    Formulation & DosageDissolved in 22% HPβCD; 100mg/kg;  Oral gavage
    References

    [1] Rowbottom MW, et al. J Med Chem, 2012, 55(3), 1082-1105. [2] James J, et al. Mol Cancer Ther, 2012, 11(4), 930-941.


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

    CEP-32496

    CEP-32496
    CEP-32496


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