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    CH5132799
    CH5132799

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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 #: V0138
    CAS #: 1007207-67-1Purity ≥98%

    Description: CH5132799 is a novel and potent class I PI3K (phosphoinositide 3-kinase) inhibitor with potential anticancer activity. It inhibits class I PI3Ks, in particular, PI3Kα with an IC50 of 14 nM, and is less potent against PI3Kβδγ, while being sensitive in PIK3CA mutated cell lines. CH5132799 shows inhibitory effects against class I PI3K with IC50 values of 0.014μM, 0.12μM, 0.5μM and 0.036μM against PI3Kα, PI3Kβ, PI3Kδ and PI3Kγ, respectively.

    References: Bioorg Med Chem Lett. 2011 Mar 15;21(6):1767-72.


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    Molecular Weight (MW)377.42
    FormulaC15H19N7O3S
    CAS No.1007207-67-1
    Storage-20℃ for 3 years in powder form
    -80℃ for 2 years in solvent
    Solubility (In vitro)DMSO: 12 mg/mL (31.79 mM)
    Water:<1 mg/mL
    Ethanol: <1 mg/mL
    Solubility (In vivo)1% DMSO+30% polyethylene glycol+1% Tween 80: 30mg/mL
    Synonyms/Chemical NameCH5132799; CH-5132799; CH 5132799; PA-799; PA799; PA-799; 5-(7-methylsulfonyl-2-morpholin-4-yl-5,6-dihydropyrrolo[2,3-d]pyrimidin-4-yl)pyrimidin-2-amine


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    In Vitro

    Kinase Assay: The E542K, E545K, and H1047R mutants of PI3Kα are prepared with an overlapped extension-polymerase chain reaction. Glutathione S-transferase-tagged PI3Kα mutants and His-tagged p85α are co-expressed with BAC-TO-BAC Baculovirus Expression System. The inhibitory activities of CH5132799 on PI3Kα (p110α/p85α), PI3Kβ(p110β/p85α), PI3Kδ (p110δ/p85α), PI3Kγ (p110γ), PI3KC2α, PI3KC2β, Vps34, and PI3Kα mutants are determined by Adapta Universal Kinase Assay Kit. Time-resolved fluorescence is measured with an EnVision HTS microplate reader. IC50 values are calculated using XLfit.

     

    Cell Assay: The cell lines are added to the wells of 96-well plates containing 0.076 to 10,000 nM CH5132799 and incubated at 37 °C. After 4 days of incubation, Cell Counting Kit-8 solution is added and, after incubation for several more hours, absorbance at 450 nm is measured with Microplate-Reader iMark. The antiproliferative activity is calculated by the formula (1- T/C) × 100 (%), in which T and C represent absorbance at 450 nm of the cells treated with CH5132799 (T) and that of untreated control cells (C). The IC50 values are calculated by using Microsoft Excel 2007. Various cancer cell lines belonging to 4 types of cancer—breast, ovarian, prostate, and endometrial cancer—in which the PIK3CA mutation and PTEN deficiency are frequently found and in which RAS/RAF is rarely mutated.

    CH5132799 selectively inhibits class I PI3Ks, PI3Kα (IC50 = 0.014 μM ), PI3Kβ (IC50 = 0.12 μM ), PI3Kδ (IC50 = 0.50 μM ), PI3Kγ (IC50 = 0.036 μM ), but shows less inhibition of class II PI3Ks, class III PI3k and mTOR and also no inhibitory activity (IC50 > 10 μM) against 26 protein kinases. CH5132799 exhibits more inhibitory activities against PI3Kα with oncogenic mutations E542K (IC50 = 6.7 nM), E545K (IC50 = 6.7 nM) and H1047R (IC50 = 5.6 nM) than wild-type PI3Kα. CH5132799 treated breast cnacer KPL-4 cells, which harbor the PIK3CA mutation, phosphorylation of Akt and its direct substrates, PRAS40 and FoxO1/3a and phosphorylation of downstream factors, including S6K, S6 and 4E-BP1, are effectively suppressed. Cancer cell lines harboring PIK3CA mutations are significantly sensitive to CH5132799 In human tumor cell lines with PI3K pathway activation by mutation, CH5132799 shows potent antiproliferative activity [HCT116(CRC): IC50 = 0.20 lM, KPL-4(BC):13 IC50 = 0.032 lM, T-47D(BC): IC50 = 0.056 lM, SK-OV-3(Ovarian): IC50 = 0.12 lM]. CH5132799 effectively suppresses phosphorylation of AKT in KPL-4 cells.

    In Vivo

    CH5132799 shows potent in vivo antitumor activity in several different xenograft models with PIK3CA mutations. CH5132799 overcomes mTORC1 inhibition-mediated Akt activation and regrowth of xenograft tumor by long-term everolimus administration. CH5132799 as a clinical candidate that shows excellent oral bioavailability (BA) (101% in mouse), human liver microsomal stability and in vivo antitumor activity in the PC-3 xenograft model (TGI: 101% at 25 mg/kg, po, q.d. × 11 days). CH5132799 exhibits good oral BA in mouse, rat, monkey and dog (F: 54.2-101%). In a human breast cancer (KPL-4: PI3Ka H1047R) xenograft model in mice, oral treatment with CH5132799 (12.5 mg/kg, q.d.) shows strong tumor regression. The strong regression is maintained during the 6 week administration, even in the intermittent dosing schedule (q.d., 2 weeks on/1 week off; q.d., 5 days on/2 days off), suggesting that a flexible administration schedule can be applicable in the clinic.

    Animal model

     A total of 4 × 106 to 1.2 × 107 cells are injected subcutaneously into the right flank of female BALB-nu/nu mice.

    Formulation & Dosage

     Dissolved in DMSO; 0.39, 0.78, 1.56, 3.13, 6.25, 12.5 and 25 mg/kg; Oral administration

    References

    [1] Tanaka H, et al, Clin Cancer Res, 2011, 17(10), 3272-3281.


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

    CH5132799

    Inhibition of PI3K pathway signaling in cells. KPL-4 cells were treated with the indicated concentrations of CH5132799 for 2 hours. Clin Cancer Res, 2011, 17(10), 3272-3281.

    CH5132799

    Antitumor activity in mouse xenograft models of cell lines harboring genetic alterations, including PIK3CA mutations
    CH5132799

    Antitumor activity in combination with trastuzumab in the trastuzumab-insensitive model.


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