NVP-BGT226

BGT226 (NVP-BGT226) is a novel inhibitor of PI3K/mTOR for PI3Kα/β/γ with IC50 of 4 nM/63 nM/38 nM. [1]
The phosphatidylinositol-3-kinase (PI3K) pathway is one of the most commonly activated signaling pathways in pancreatic cancer and is a target of interest for new therapeutic approaches.
NVP-BGT226 is a novel dual class PI3K/mammalian target of rapamycin (mTOR) inhibitor. When used NVP-BGT226, cell viability decreased within 24-72 h after exposure to about 50% compared to untreated control cells in a concentration- but not time-dependent manner. [1] The dual PI3K/mTOR inhibitor NVP-BGT226 induces G0/G1 arrest and acts partially via downregulation of Survivin. NVP-BGT226 potently inhibited growth activity of cell lines, including SCC4, TU183 and KB cell lines with the IC50 ranging from 7.4 to 30.1 nM. [2]
In a FaDu cell xenografted mouse model, BGT226 inhibited tumor growth in a dose-dependent manner in a FaDu cell xenografted mouse model. 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 on day 21, respectively (compared with control). BGT226 displayed comparable inhibition against tumor growth to rapamycin. The final volume of both groups was significantly smaller than those treated with LY294002 or the control. [2]
References:
[1]. Glienke, W, et al. The dual PI3K/mTOR inhibitor NVP-BGT226 induces cell cycle arrest and regulates Survivin gene expression in human pancreatic cancer cell lines. TUMOR BIOLOGY, 2014, 33(3): 757-765.
[2]. Chang KY, et al. 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, 17(22): 7116-7126.

The novel dual PI3K/mTOR inhibitor NVP-BGT226 displays cytotoxic activity in both normoxic and hypoxic hepatocarcinoma cells.[Pubmed:26003166]

Oncotarget. 2015 Jul 10;6(19):17147-60.

Hepatocellular carcinoma (HCC) is one of the most common lethal human malignancies worldwide and its advanced status is frequently resistant to conventional chemotherapeutic agents and radiation. We evaluated the cytotoxic effect of the orally bioavailable dual PI3K/mTOR inhibitor, NVP-BGT226, on a panel of HCC cell lines, since hyperactivated PI3K/Akt/mTOR signaling pathway could represent a biomolecular target for Small Inhibitor Molecules in this neoplasia. We analyzed the drug activity in both normoxia and hypoxia conditions, the latter playing often a relevant role in the induction of chemoresistance and angiogenesis.In normoxia NVP-BGT226 caused cell cycle arrest in the G0/G1 phase of the cell cycle, induced apoptosis and autophagy at low concentrations. Interestingly the drug inactivated p-Akt and p-S6 at < 10 nM concentration.In hypoxia NVP-BGT226 maintained its cytotoxic efficacy at the same concentration as documented by MTT assays and Western blot analysis. Moreover, the drug showed in hypoxia inhibitory properties against angiogenesis by lowering the expression of the transcription factor HIF-1alpha and of VEGF.Our results indicate that NVP-BGT226 has a potent cytotoxic effect on HCC cell lines also in hypoxia condition, thus emerging as a potential candidate for cancer treatment in HCC targeted therapy.

The dual PI3K/mTOR inhibitor NVP-BGT226 induces cell cycle arrest and regulates Survivin gene expression in human pancreatic cancer cell lines.[Pubmed:22170433]

Tumour Biol. 2012 Jun;33(3):757-65.

The phosphatidylinositol-3-kinase (PI3K) pathway is one of the most commonly activated signaling pathways in pancreatic cancer and is a target of interest for new therapeutic approaches. NVP-BGT226 is a novel dual class PI3K/mammalian target of rapamycin (mTOR) inhibitor that has entered Phase I/II clinical trials. We analyzed the effect of NVP-BGT226 (10-100 nM) on the pancreatic cell lines Panc-1, BxPc-3, AsPC-1 and MiaPaCa-2 in regard to cell viability, induction of apoptosis, cell cycle, and expression of the antiapoptotic genes Survivin, MCL-1, BCL-2 and BCL-xL. Cell viability decreased within 24-72 h after exposure to about 50% compared to untreated control cells in a concentration- but not time-dependent manner. Cell cycle analysis revealed that NVP-BGT226 induced predominantly G0/G1 cell cycle arrest. Additionally, real-time RT-PCR and Western blot analysis showed a remarkable decrease of Survivin expression. Originally designed as a dual inhibitor, there was only a significant inhibition of p-mTOR. In summary, the dual PI3K/mTOR inhibitor NVP-BGT226 induces G0/G1 arrest and acts, at least, partially via downregulation of Survivin.

NVP-BEZ235 and NVP-BGT226, dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitors, enhance tumor and endothelial cell radiosensitivity.[Pubmed:22452803]

Radiat Oncol. 2012 Mar 27;7:48.

BACKGROUND: The phosphatidylinositol 3-kinase (PI3K)/Akt pathway is activated in tumor cells and promotes tumor cell survival after radiation-induced DNA damage. 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. MATERIALS AND METHODS: We investigated the effect of two dual PI3K/mTOR (both mTORC1 and mTORC2) inhibitors, NVP-BEZ235 and NVP-BGT226, on SQ20B laryngeal and FaDu hypopharyngeal cancer cells characterised by EGFR overexpression, on T24 bladder tumor cell lines with H-Ras mutation and on endothelial cells. Analysis of target protein phosphorylation, clonogenic survival, number of residual gammaH2AX foci, cell cycle and apoptosis after radiation was performed in both tumor and endothelial cells. In vitro angiogenesis assays were conducted as well. RESULTS: Both compounds effectively inhibited phosphorylation of Akt, mTOR and S6 target proteins and reduced clonogenic survival in irradiated tumor cells. Persistence of DNA damage, as evidenced by increased number of gammaH2AX foci, was detected after irradiation in the presence of PI3K/mTOR inhibition, together with enhanced G2 cell cycle delay. Treatment with one of the inhibitors, NVP-BEZ235, also resulted in decreased clonogenicity after irradiation of tumor cells under hypoxic conditions. In addition, NVP-BEZ235 blocked VEGF- and IR-induced Akt phosphorylation and increased radiation killing in human umbilical venous endothelial cells (HUVEC) and human dermal microvascular dermal cells (HDMVC). NVP-BEZ235 inhibited VEGF-induced cell migration and capillary tube formation in vitro and enhanced the antivascular effect of irradiation. Treatment with NVP-BEZ235 moderately increased apoptosis in SQ20B and HUVEC cells but not in FaDu cells, and increased necrosis in both tumor and endothelial all cells tumor. CONCLUSIONS: The results of this study demonstrate that PI3K/mTOR inhibitors can enhance radiation-induced killing in tumor and endothelial cells and may be of benefit when combined with radiotherapy.

Cell cycle-dependent activity of the novel dual PI3K-MTORC1/2 inhibitor NVP-BGT226 in acute leukemia.[Pubmed:23705826]

Mol Cancer. 2013 May 24;12:46.

BACKGROUND: Dysregulation of the PI3Kinase/AKT pathway is involved in the pathogenesis of many human malignancies. In acute leukemia, the AKT pathway is frequently activated, however mutations in the PI3K/AKT pathway are uncommon. In some cases, constitutive AKT activation can be linked to gain-of-function tyrosine kinase (TK) mutations upstream of the PI3K/AKT pathway. Inhibitors of the PI3K/AKT pathway are attractive candidates for cancer drug development, but so far clinical efficacy of PI3K inhibitors against various neoplasms has been moderate. Furthermore, specific MTORC1 inhibitors, acting downstream of AKT, have the disadvantage of activating AKT via feed-back mechanisms. We now evaluated the antitumor efficacy of NVP-BGT226, a novel dual pan-PI3K and MTORC1/2 inhibitor, in acute leukemia. METHODS: Native leukemia blasts were stained to analyze for AKT phosphorylation levels on a flow cytometer. Efficacy of NVP-BGT226 in comparison to a second dual inhibitor, NVP-BEZ235, was determined with regard to cellular proliferation, autophagy, cell cycle regulation and induction of apoptosis in in vitro and ex vivo cellular assays as well as on the protein level. An isogenic AKT-autoactivated Ba/F3 model, different human leukemia cell lines as well as native leukemia patient blasts were studied. Isobologram analyses were set up to calculate for (super) additive or antagonistic effects of two agents. RESULTS: We show, that phosphorylation of AKT is frequently augmented in acute leukemia. NVP-BGT226 as well as NVP-BEZ235 profoundly and globally suppress AKT signaling pathways, which translates into potent antiproliferative effects. Furthermore, NVP-BGT226 has potent proapoptotic effects in vitro as well as in ex vivo native blasts. Surprisingly and in contrast, NVP-BEZ235 leads to a profound G1/G0 arrest preventing significant induction of apoptosis. Combination with TK inhibitors, which are currently been tested in the treatment of acute leukemia subtypes, overcomes cell cycle arrest and results in (super)additive proapoptotic effects for NVP-BGT226--but also for NVP-BEZ235. Importantly, mononuclear donor cells show lower phospho-AKT expression levels and consequently, relative insensitivity towards dual PI3K-MTORC1/2 inhibition. CONCLUSIONS: Our data suggest a favorable antileukemic profile for NVP-BGT226 compared to NVP-BEZ235--which provides a strong rationale for clinical evaluation of the dual PI3K-MTORC1/2 inhibitor NVP-BGT226 in acute leukemia.

BGT226 maleate (NVP-BGT226 maleate) is a PI3K (with IC50s of 4 nM, 63 nM and 38 nM for PI3Kα, PI3Kβ and PI3Kγ) /mTOR dual inhibitor which displays potent growth-inhibitory activity against human head and neck cancer cells.

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