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BGT226 maleate

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Chemical Structure| 1245537-68-1 同义名 : NVP-BGT226;NVP-BGT226 maleate
CAS号 : 1245537-68-1
货号 : A514784
分子式 : C32H29F3N6O6
纯度 : 99%+
分子量 : 650.605
MDL号 : MFCD22124895
存储条件：

粉末 Inert atmosphere,Store in freezer, under -20°C

液体 -20°C:3-6个月-80°C:12个月
溶解度 :

DMSO: 60 mg/mL(92.22 mM)，配合低频超声，并水浴加热至45℃助溶，注意：DMSO长时间开封后，会吸水并导致溶解能力下降，请避免使用长期开封的DMSO
动物实验配方：

PO 0.5% CMC-Na 62 mg/mL suspension

生物活性
靶点

  • p110γ

    PI3Kγ, IC50:38 nM

  • p110β

    PI3Kβ, IC50:63 nM

  • p110α

    PI3Kα, IC50:4 nM

  • mTOR
描述 The phosphoinositide 3-kinase (PI3K)/Akt/mTOR signaling pathway is one of the most frequently dysregulated signaling cascades in human malignancies, it displays oncogenic potential and it is implicated in a wide variety of different neoplasms. NVP-BGT226 (BGT226), an imidazoquinoline derivative, an ATP-competitive dual PI3K/mTORC1/C2 inhibitor: it is a potent pan-class I PI3K inhibitor (p110α, β, δ, and γ, with a preference for the α-isoform -wild type and mutated-) and is a mTORC1/2 catalytic inhibitor. The IC50s of NVP-BGT226 is 4 nM, 63 nM and 38 nM for PI3Kα, PI3Kβ and PI3Kγ[3]. Because the pathway may not be completely inhibited after blockade of PI3K itself, due to feedback through mammalian target of rapamycin (mTOR), more effective inhibition might be expected by targeting both PI3K and mTOR inhibition. There is extensive crosstalk between the two signalling networks. mTOR can affect PI3K/Akt signalling through the S6K-IRS1 feedback loop and induce Akt phosphorylation by mTORC2. NVP-BGT226 can effectively block downstream targets and result in radiation sensitization in tumor cell lines and in endothelial cells[4]. BGT226 could affect the viability of HCC cell lines, Mahlavu, SNU475, SNU449, HepG2 and Hep3B cells when they were incubated in the presence of increasing concentrations of the drug from 0.50 μM to 1.5 μM for either 24 or 48h. The experiments documented that already at 24h all the cell lines were very sensitive to BGT226. After 48h of treatment cell viability impairment was more evident, with an IC50 value ranging from 0.55 μM for Mahlavu to 1.35 μM for HepG2 cell[5]. Oral administration of BGT226 at 2.5 and 5 mg/kg for 3 weeks caused 34.7% and 76.1% reduction of the tumor growth in the human FaDu xenografted mice on day 21, respectively (compared with control)[6].
实验方案
1mg 5mg 10mg

1 mM

5 mM

10 mM

1.54mL

0.31mL

0.15mL

7.69mL

1.54mL

0.77mL

15.37mL

3.07mL

1.54mL
参考文献

[1]Markman B, Tabernero J, et al. Phase I safety, pharmacokinetic, and pharmacodynamic study of the oral phosphatidylinositol-3-kinase and mTOR inhibitor BGT226 in patients with advanced solid tumors. Ann Oncol. 2012 Sep;23(9):2399-408.

[2]Baumann P, Schneider L, et al. Simultaneous targeting of PI3K and mTOR with NVP-BGT226 is highly effective in multiple myeloma. Anticancer Drugs. 2012 Jan;23(1):131-8.

[3]Markman B, Tabernero J, Krop I, Shapiro GI, Siu L, Chen LC, Mita M, Melendez Cuero M, Stutvoet S, Birle D, Anak Ö, Hackl W, Baselga J. Phase I safety, pharmacokinetic, and pharmacodynamic study of the oral phosphatidylinositol-3-kinase and mTOR inhibitor BGT226 in patients with advanced solid tumors. Ann Oncol. 2012 Sep;23(9):2399-2408. doi: 10.1093/annonc/mds011. Epub 2012 Feb 22. PMID: 22357447.

[4]Fokas E, Yoshimura M, Prevo R, Higgins G, Hackl W, Maira SM, Bernhard EJ, McKenna WG, Muschel RJ. NVP-BEZ235 and NVP-BGT226, dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitors, enhance tumor and endothelial cell radiosensitivity. Radiat Oncol. 2012 Mar 27;7:48. doi: 10.1186/1748-717X-7-48. PMID: 22452803; PMCID: PMC3348043.

[5]Simioni C, Cani A, Martelli AM, Zauli G, Alameen AA, Ultimo S, Tabellini G, McCubrey JA, Capitani S, Neri LM. The novel dual PI3K/mTOR inhibitor NVP-BGT226 displays cytotoxic activity in both normoxic and hypoxic hepatocarcinoma cells. Oncotarget. 2015 Jul 10;6(19):17147-60. doi: 10.18632/oncotarget.3940. PMID: 26003166; PMCID: PMC4627298.

[6]Chang KY, Tsai SY, Wu CM, Yen CJ, Chuang BF, Chang JY. Novel phosphoinositide 3-kinase/mTOR dual inhibitor, NVP-BGT226, displays potent growth-inhibitory activity against human head and neck cancer cells in vitro and in vivo. Clin Cancer Res. 2011 Nov 15;17(22):7116-26. doi: 10.1158/1078-0432.CCR-11-0796. Epub 2011 Oct 5. PMID: 21976531.