BGT226 (NVP-BGT226)

Catalog No.S2749

BGT226 (NVP-BGT226) is a novel class I PI3K/mTOR inhibitor for PI3Kα/β/γ with IC50 of 4 nM/63 nM/38 nM. Phase 1/2.

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BGT226 (NVP-BGT226) Chemical Structure

BGT226 (NVP-BGT226) Chemical Structure
Molecular Weight: 650.6

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Product Description

Biological Activity

Description BGT226 (NVP-BGT226) is a novel class I PI3K/mTOR inhibitor for PI3Kα/β/γ with IC50 of 4 nM/63 nM/38 nM. Phase 1/2.
Targets mTOR [1] PI3Kα [1] PI3Kγ [1] PI3Kβ [1]
IC50 4 nM 38 nM 63 nM
In vitro The anti-proliferative and pro-apoptotic effects of NVP-BGT226 are independent of bcr-abl status. The activation of the AKT/mTOR signal cascade is suppressed by NVP-BGT226 in a concentration- and time-dependent manner. Flow cytometric analysis exhibits an accumulation of cells in the G(0)-G(1) phase with concomitant loss in the S-phase. NVP-BGT226 displays potent growth-inhibitory activity against all tested cell lines including SCC4, TU183 and KB cell lines with the IC50 ranging from 7.4 to 30.1 nM. Notably, both Detroit 562 and HONE-1 cells, which express PIK3CA mutation H1047R, are still sensitive to the growth-inhibitory effect of NVP-BGT226 treatment. In addition, the sensitivity to NVP-BGT226 between HONE-1 cells and its cisplatin-resistant variant is almost identical. Results of the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay and the analysis of caspase 3/7 and PARP indicates that NVP-BGT226 induces cancer cell death through an apoptosis-independent pathway. NVP-BGT226 induces autophagy as indicated by the aggregation and upregulation of the microtubule-associated protein light chain 3B-II, and p62 degradation. Gene silencing of Beclin1 or cotreatment of the autophagosome inhibitor, 3-methyladenine, inhibits the NVP-BGT226-induced autophagy and leads to the retrieval of colony survival.[2] NVP-BGT226 inhibits growth in common myeloma cell lines and primary myeloma cells (such as NCI-H929, U266, RPMI-8226 and OPM2 MM cell lines) at nanomolar concentrations in a time-dependent and dose-dependent manner. NVP-BGT226 inhibits phosphorylation of protein kinase B (Akt), P70S6k and 4E-BP-1 in a time-dependent and dose-dependent manner. The stimulatory effect of insulin-like growth factor 1, interleukin-6 and conditioned medium of HS-5 stromal cells on myeloma cell growth is completely abrogated by NVP-BGT226. Inhibition of phosphoinositol-3-kinase/mammalian target of rapamycin by NVP-BGT226 is highly effective, and NVP-BGT226 represents a potential new candidate for targeted therapy in multiple myeloma. Combined inhibition of PI3K and mammalian target of rapamycin (mTOR) by NVP-BGT226 has been proven to be very effective in terms of induction of apoptosis and inhibition of proliferation. [3] In another study, after 24 hours, 86.9% MiaPaCa-2 100 nM NVP-BGT226 treated cells arrests at the G0/G1 phase compared to 55.6% of control cells. [4]
In vivo In a xenografted animal model, NVP-BGT226 significantly delays tumor growth in a dose-dependent manner, along with suppressed cytoplasmic expression of p-p70 S6 kinase and the presence of autophagosome formation. NVP-BGT226 inhibits tumor growth in a dose-dependent manner in a FaDu cell xenografted mouse model. Oral administration of NVP-BGT226 at 2.5 and 5 mg/kg for 3 weeks causes 34.7% and 76.1% reduction of the tumor growth on day 21, respectively (compared with control). NVP-BGT226 displays comparable inhibition against tumor growth to rapamycin. The final volume of both groups is significantly smaller than those treated with LY294002 (a PI3K inhibitor) or the control. [2]
Features

Protocol(Only for Reference)

Cell Assay: [3]

Cell lines NCI-H929, U266, RPMI-8226 and OPM2 MM cells
Concentrations 20-250 nM
Incubation Time 36 hours
Method NCI-H929, U266, RPMI-8226 and OPM2 MM cells are seeded in 96-well plates at a concentration of 1.5 × 104 cells/well in RPMI medium supplemented with 10% fetal bovine serum with or without NVP-BGT226 that is to be tested. After 36 hours, BrdU-labelling solution is added (final concentration: 10 μM), and cells are cultured for another 12 hours in a humidified atmosphere (37 °C/5% CO2). Then, the plates are centrifuged (10 min, 300 g), and the supernatants are discarded. The plates are dried at 60 °C for 2 hours. After fixation with ethanol/HCl for 30 min at -20 °C, the DNA is partially digested by nuclease treatment for 30 min at 37 °C. The cells are washed three times with medium and incubated with anti-BrdU-POD labelling solution for 30 min at 37 °C. The anti-POD solution is removed and the cells are washed three times with washing buffer. The ABTS substrate solution is added, and absorbance is measured in a microplate reader at 405 nm with a reference wave length of 490 nm.

Animal Study: [2]

Animal Models Human FaDu xenografted mice
Formulation 90% N -methyl-2-pyrrolidone (NMP)/10% PEG300
Dosages 5 mg/kg for 3 weeks
Administration Oral administration

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] Markman B, et al. Ann Oncol, 2012, 23(9), 2399-2408.

[2] Chang KY, et al. Clin Cancer Res, 2011, 17(22), 7116-7126.

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

NCT Number Recruitment Conditions Sponsor
/Collaborators
Start Date Phases
NCT00742105 Completed Cancer|Solid Tumor|Advanced Solid Tumor Novartis Pharmaceuticals|Novartis November 2008 Phase 1
NCT00600275 Completed Solid Tumors|Breast Cancer|Cowden Syndrome Novartis Pharmaceuticals|Novartis December 2007 Phase 1|Phase 2

Chemical Information

Download BGT226 (NVP-BGT226) SDF
Molecular Weight (MW) 650.6
Formula

C28H25F3N6O2.C4H4O4

CAS No. 1245537-68-1
Storage 3 years -20℃powder
6 months-80℃in solvent
Synonyms N/A
Solubility (25°C) * In vitro DMSO 30 mg/mL (46.11 mM)
Water <1 mg/mL (<1 mM)
Ethanol <1 mg/mL (<1 mM)
In vivo 30% PEG400+0.5% Tween80+5% propylene glycol 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 8-(6-methoxypyridin-3-yl)-3-methyl-1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)-1H-imidazo[4,5-c]quinolin-2(3H)-one Maleic acid

Customer Product Validation(3)


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Rating
Source Cancer Lett 2014 348(1-2), 38-49. BGT226 (NVP-BGT226) purchased from Selleck
Method Western blot
Cell Lines IGROV1-10R cells
Concentrations 250 nM
Incubation Time 8 h
Results An 8 h treatment with 250 nM BGT226 alone drastically inhibited PI3K/Akt/mTOR pathway activation, reduced Mcl-1 expression and up-regulated Bim expression.

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Rating
Source PLoS One 2014 9(3), e90746. BGT226 (NVP-BGT226) purchased from Selleck
Method Immunostaining
Cell Lines SCC61 cells
Concentrations 300 nM
Incubation Time 24 h
Results Representative images of SCC61 cells after 24 hours of treatment provide qualitative visualization of the redox ratio, NADH α1, and FAD α1. NADH and FAD fluorescence from the cytoplasm was quantified across treatment groups and cell lines. The redox ratios of SCC61 cells show no significant changes with cetuximab treatment, and decrease with BGT226 and cisplatin treatment. The fluorescence lifetimes of NADH and FAD reflect cellular microenvironment and protein-binding. NADH α1 represents the contribution from free NADH. For SCC25 cells, NADH α1 decreases with BGT226 and cisplatin treatment. For SCC61 cells, NADH α1 decreases with cetuximab, BGT226, and cisplatin treatment.

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Rating
Source PLoS One 2014 9(3), e90746. BGT226 (NVP-BGT226) purchased from Selleck
Method Western blotting
Cell Lines SCC61 cells
Concentrations 300 nM
Incubation Time 24 h
Results Western blotting analysis was used to ensure target inhibition. BGT226 targeting of PI3K/mTOR was assessed by measuring phosphorylated serine (S) 473 of Akt (pAkt) because PI3K and mTOR activation drive Akt activation in the PI3K/Akt signaling pathway. pAkt is absent with BGT226 treatment. These results indicate that BGT226 target EGFR and PI3K/mTOR. SCC61 cells showed increased pAkt, reflecting upregulated PI3K, and agreeing with published results. Additionally, SCC61 cells exhibited increased EGFR and pEGFR.

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