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Synonyms | N/A | Storage (From the date of receipt) |
3 years -20°C powder 1 years -80°C in solvent |
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化学式 | C28H25F3N6O2.C4H4O |
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分子量 | 650.6 | CAS No. | 1245537-68-1 | ||||
Solubility (25°C)* | 体外 | DMSO | 30 mg/mL (46.11 mM) | ||||
Water | Insoluble | ||||||
Ethanol | Insoluble | ||||||
体内 (毎回新しく調製した物を用意してください) |
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* <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. |
製品説明 | 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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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] |
細胞アッセイ | 細胞株 | NCI-H929, U266, RPMI-8226 and OPM2 MM cells |
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濃度 | 20-250 nM | |
反応時間 | 36 hours | |
実験の流れ | 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. | |
動物実験 | 動物モデル | Human FaDu xenografted mice |
投薬量 | 5 mg/kg for 3 weeks | |
投与方法 | Oral administration |
Data from [Cancer Lett, 2014, 348(1-2), 38-49]
Data from [Data independently produced by PLoS One, 2014, 9(3), e90746]
Data from [Data independently produced by PLoS One, 2014, 9(3), e90746]
PIK Your Poison: The Effects of Combining PI3K and CDK Inhibitors against Metastatic Cutaneous Squamous Cell Carcinoma In Vitro [ Cancers (Basel), 2024, 16(2)370] | PubMed: 38254859 |
High-throughput and targeted drug screens identify pharmacological candidates against MiT-translocation renal cell carcinoma [ J Exp Clin Cancer Res, 2023, 42(1):99] | PubMed: 37095531 |
A high-throughput screening platform identifies novel combination treatments for Malignant Peripheral Nerve Sheath Tumors [ Mol Cancer Ther, 2022, molcanther.MCT-21-0947-A.2021] | PubMed: 35511749 |
Co-targeting PI3K, mTOR, and IGF1R with small molecule inhibitors for treating undifferentiated pleomorphic sarcoma. [ Cancer Biol Ther, 2017, 18(10):816-826] | PubMed: 29099264 |
Healthy CD4+ T lymphocytes are not affected by targeted therapies against the PI3K/Akt/mTOR pathway in T-cell acute lymphoblastic leukemia. [ Oncotarget, 2016, 7(34):55690-55703] | PubMed: 27494886 |
Synergistic effects of selective inhibitors targeting the PI3K/AKT/mTOR pathway or NUP214-ABL1 fusion protein in human Acute Lymphoblastic Leukemia. [Simioni C, et al. Oncotarget, 2016, 7(48):79842-79853] | PubMed: 27821800 |
The PI3K/Akt Pathway Regulates Oxygen Metabolism via Pyruvate Dehydrogenase (PDH)-E1α Phosphorylation [Cerniglia GJ, et al. Mol Cancer Ther, 2015, 14(8):1928-38] | PubMed: 25995437 |
The novel dual PI3K/mTOR inhibitor NVP-BGT226 displays cytotoxic activity in both normoxic and hypoxic hepatocarcinoma cells. [Simioni C, et al. Oncotarget, 2015, 6(19):17147-60] | PubMed: 26003166 |
PI3K/mTOR dual inhibitor NVP-BEZ235 decreases Mcl-1 expression and sensitizes ovarian carcinoma cells to Bcl-x L -targeting strategies provided that Bim expression is induced [Jebahi A et al. Cancer Lett, 2014, 348(1-2):38-49] | PubMed: 24650799 |
Optical metabolic imaging of treatment response in human head and neck squamous cell carcinoma. [Shah AT PLoS One, 2014, 9(3):e90746] | PubMed: 24595244 |
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