CH5132799

Catalog No.S2699

CH5132799 inhibits class I PI3Ks, particularly PI3Kα with IC50 of 14 nM; less potent to PI3Kβδγ, while sensitive in PIK3CA mutations cell lines. Phase 1.

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CH5132799 Chemical Structure

CH5132799 Chemical Structure
Molecular Weight: 377.42

Validation & Quality Control

2 customer reviews :

Quality Control & MSDS

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  • CH5132799 Mechanism

Product Description

Biological Activity

Description CH5132799 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]

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IC50 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]
Features

Protocol(Only for 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.
Formulation CH5132799 is dissolved in DMSO.
Dosages 0.39, 0.78, 1.56, 3.13, 6.25, 12.5 and 25 mg/kg
Administration Orally administered once a day.

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

SpeciesMouseRatRabbitGuinea pigHamsterDog
Weight (kg)0.020.151.80.40.0810
Body Surface Area (m2)0.0070.0250.150.050.020.5
Km factor36128520
Animal A (mg/kg) = Animal B (mg/kg) multiplied by  Animal B Km
Animal A Km

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×  mouse Km(3)  = 11.2 mg/kg
rat Km(6)
1

References

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

[2] Ohwada J, et al, Bioorg Med Chem Leff, 2011, 21(6), 1767-1772.

Clinical Trial Information( data from http://clinicaltrials.gov, updated on 2016-07-23)

NCT Number Recruitment Conditions Sponsor
/Collaborators
Start Date Phases
NCT01222546 Completed Solid Tumors Chugai Pharma Europe Ltd. August 2010 Phase 1

Chemical Information

Download CH5132799 SDF
Molecular Weight (MW) 377.42
Formula

C15H19N7O3S

CAS No. 1007207-67-1
Storage 3 years -20℃powder
6 months-80℃in solvent
Synonyms N/A
Solubility (25°C) * In vitro DMSO 12 mg/mL (31.79 mM)
Water <1 mg/mL (<1 mM)
Ethanol <1 mg/mL (<1 mM)
In vivo 1% DMSO+30% polyethylene glycol+1% Tween 80 30 mg/mL
* <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.
Chemical Name 5-(7-(methylsulfonyl)-2-morpholino-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrimidin-2-amine

Customer Product Validation(2)


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Rating
Source Biochimie 2014 105, 182-91. CH5132799 purchased from Selleck
Method Western blot
Cell Lines Platelet
Concentrations 10 uM
Incubation Time 10 min
Results Thus to deeply investigate the mechanisms involved it wanted to verify if PI3K could participate in MLC phosphorylation. It found that MLC phosphorylation induced by 2-AG was cancelled by the generic PI3K inhibitor LY294002 and was partially reduced (by about 50%) by CH5132799 or TGX221, which can be considered specific inhibitors of the PI3Kα or PI3Kβ isoform, respectively. The effect was complete in platelet pretreated with CH5132799 and TGX221 added at the same time.

Click to enlarge
Rating
Source CH5132799 purchased from Selleck
Method Western blot
Cell Lines A549 cells
Concentrations 1-20 uM
Incubation Time 24 h
Results This PI3K inhibitor dramatically reduced AKT phosphorylation at 10uM.

Tech Support

Answers to questions you may have can be found in the inhibitor handling instructions. Topics include how to prepare stock solutions, how to store inhibitors, and issues that need special attention for cell-based assays and animal experiments.

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
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