CH5132799

Catalog No.S2699 Batch:S269902

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Technical Data

Formula

C15H19N7O3S
Molecular Weight 377.42 CAS No. 1007207-67-1
Solubility (25°C)* In vitro DMSO 12 mg/mL (31.79 mM)
Water Insoluble
Ethanol Insoluble
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
* Room temperature shipping (Stability testing shows this product can be shipped without any cooling measures.)

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Biological Activity

Description CH5132799 (MEN1611, PA799) inhibits class I PI3Ks, particularly PI3Kα with IC50 of 14 nM; less potent to PI3Kβδγ, while sensitive in PIK3CA mutations cell lines. Phase 1.
Targets
PI3Kα [1] PI3Kγ [1] PI3Kβ [1] PI3Kδ [1]
14 nM 36 nM 0.12 μM 0.50 μM
In vitro 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 [1] 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. [2]
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. [1] 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. [2]

Protocol (from reference)

Kinase Assay:

[1]
  • PI3K 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:

[1]
  • Cell lines

    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

  • Concentrations

    0 - 10μM

  • Incubation Time

    4 days

  • Method

    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.
Animal Study:

[1]
  • Animal Models

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

  • Dosages

    0.39, 0.78, 1.56, 3.13, 6.25, 12.5 and 25 mg/kg

  • Administration

    Orally administered once a day.

Customer Product Validation

Data from [Data independently produced by Biochimie, 2014, 105, 182-91]

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Selleck's CH5132799 has been cited by 4 publications

Examining PI3K-signaling-dependent regulation of lens organelle free zone formation via immunolocalization and immunoblotting in chick embryos [ STAR Protoc, 2023, 10.1016/j.xpro.2023.102569] PubMed: 37713308
Examining PI3K-signaling-dependent regulation of lens organelle free zone formation via immunolocalization and immunoblotting in chick embryos [ STAR Protoc, 2023, 4(4):102569] PubMed: 37713308
Effect of 2-arachidonoylglycerol on myosin light chain phosphorylation and platelet activation: The role of phosphatidylinositol 3 kinase/AKT pathway [Signorello MG et al. Biochimie, 2014, 105:182-91] PubMed: 25068972
A chemical biology approach identified PI3K as a potential therapeutic target for neurofibromatosis type 2. [Petrilli AM, et al. Am J Transl Res, 2014, 6(5):471-493] PubMed: 25360213

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SHIPPING AND STORAGE
Selleck products are transported at room temperature. If you receive the product at room temperature, please rest assured, the Selleck Quality Inspection Department has conducted experiments to verify that the normal temperature placement of one month will not affect the biological activity of powder products. After collecting, please store the product according to the requirements described in the datasheet. Most Selleck products are stable under the recommended conditions.

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