BGT226
(Synonyms: NVP-BGT226) 目录号 : GC35509
BGT226 (NVP-BGT226) maleate is a novel class I PI3K/mTOR inhibitor for PI3Kα/β/γ with IC50 of 4 nM/63 nM/38 nM. Phase 1/2.
Cas No.:915020-55-2
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
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BGT226 (NVP-BGT226) maleate is a novel class I PI3K/mTOR inhibitor for PI3Kα/β/γ with IC50 of 4 nM/63 nM/38 nM. Phase 1/2.
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 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]
[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. [3] Baumann P, et al. Anticancer Drugs, 2012, 23(1), 131-138.
| Cas No. | 915020-55-2 | SDF | |
| 别名 | NVP-BGT226 | ||
| Canonical SMILES | O=C(N1C2=CC=C(N3CCNCC3)C(C(F)(F)F)=C2)N(C)C4=C1C5=CC(C6=CC=C(OC)N=C6)=CC=C5N=C4 | ||
| 分子式 | C28H25F3N6O2 | 分子量 | 534.53 |
| 溶解度 | Soluble in DMSO | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 1.8708 mL | 9.354 mL | 18.708 mL |
| 5 mM | 0.3742 mL | 1.8708 mL | 3.7416 mL |
| 10 mM | 0.1871 mL | 0.9354 mL | 1.8708 mL |
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| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
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| % DMSO % % Tween 80 % saline | ||||||||||
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工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
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3. 以上所有助溶剂都可在 GlpBio 网站选购。
Phase I study of BGT226, a pan-PI3K and mTOR inhibitor, in Japanese patients with advanced solid cancers
Cancer Chemother Pharmacol 2019 Aug;84(2):337-343.PMID:31190275DOI:10.1007/s00280-019-03883-6.
The phosphatidylinositol 3-kinase (PI3K) pathway is a promising therapeutic target for various cancers. BGT226 is a pan-PI3K and mammalian target of rapamycin (mTOR) inhibitor. The tolerability and pharmacokinetics/pharmacodynamics of BGT226 were investigated in a phase I study in Japanese patients with advanced solid cancers. BGT226 was orally administered on days 1, 3, and 5 of each week. The initial dose of 10 mg was subsequently escalated to 20, 40, 80, and 100 mg in a cohort of three patients. Pharmacokinetics and pharmacodynamics were investigated using plasma, normal skin, and tumor samples. A total of 18 patients were enrolled and evaluated. The most frequently reported toxicities were diarrhea, nausea, decreased appetite, vomiting, and fatigue. They were all grade 1 or 2, and no dose-limiting toxicity was observed. However, all six patients treated at 100 mg experienced diarrhea and nausea, while two experienced a dose reduction and/or interruptions during the study. Two of five patients who exhibited stable disease continued the study treatment for ≥ 16 weeks. The absorption of BGT226 was rapid, and systemic exposure increased in a dose-dependent manner. Treatment with BGT226 did not change any of the biomarkers in neither normal skin nor tumor tissues. BGT226 was tolerated up to 100 mg three times a week in Japanese patients with solid cancers, without difference in toxicity profiles and pharmacokinetics compared to Western patients.
CC-223, NSC781406, and BGT226 Exerts a Cytotoxic Effect Against Pancreatic Cancer Cells via mTOR Signaling
Front Pharmacol 2020 Nov 11;11:580407.PMID:33343350DOI:10.3389/fphar.2020.580407.
The mTOR signaling pathway is abnormally activated in pancreatic cancer and is related to tumor glucose metabolism. However, its specific regulation mechanism is still unclear. Therefore, this study aims to investigate whether Sestrin2 affects the glucose metabolism of pancreatic cancer by modulating mTOR signal and then affects its biological behavior. We have observed that l-leucine can promote the proliferation of pancreatic cancer cells and increase the expression of Sestrin2 and p-mTOR proteins. In order to further study the role of Sestrin2 and mTOR signaling in pancreatic cancer, we conducted Sestrin2 overexpression and mTOR pharmacological inhibition experiments. We found that Sestrin2 overexpression can increase glycolysis of pancreatic cancer cells and promote their proliferation. This effect can be eliminated by mTOR inhibitors. Finally, we found that Sestrin2 knockdown could inhibit the growth of pancreatic cancer in vivo. In conclusion, these findings suggest that Sestrin2 may promote the occurrence and development of pancreatic cancer through mTOR signaling.
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.PMID:21976531DOI:10.1158/1078-0432.CCR-11-0796.
Purpose: Dysregulation of the phosphoinositide 3-kinase (PI3K)/AKT/mTOR signaling pathway frequently accounts for the tumorigenesis in head and neck cancer. To develop a new treatment, we investigated the effect of a novel dual PI3K/mTOR inhibitor, NVP-BGT226 (BGT226), in head and neck cancer cells. Experimental design: The in vitro antitumor effect of BGT226 was determined in various cancer cell lines. Animal models were also applied to examine drug potency. The inhibitory ability of BGT226 on the PI3K/AKT/mTOR signaling pathway was analyzed. Results: The growth inhibition assay revealed that BGT226 was active against all tested cancer cell lines. Cross-resistance was not observed in the cisplatin-resistant cell line. The activation of the AKT/mTOR signal cascade was suppressed by BGT226 in a concentration- and time-dependent manner. Flow cytometric analysis revealed an accumulation of cells in the G(0)-G(1) phase with concomitant loss in the S-phase. Results of the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay and the analysis of caspase 3/7 and PARP indicated that BGT226 induced cancer cell death through an apoptosis-independent pathway. BGT226 induced 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, inhibited the BGT226-induced autophagy and led to the retrieval of colony survival. In a xenografted animal model, BGT226 significantly delayed tumor growth in a dose-dependent manner, along with suppressed cytoplasmic expression of p-p70 S6 kinase and the presence of autophagosome formation. Conclusions: These data indicate that BGT226 is a potential drug in the treatment of head and neck cancer.
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.PMID:22357447DOI:10.1093/annonc/mds011.
Background: This phase I dose-escalation study investigated the maximum tolerated dose (MTD), safety, pharmacokinetics, pharmacodynamics (PDs), and preliminary antitumor activity of BGT226, a potent, oral dual phosphatidylinositol-3-kinase (PI3K)/mammalian target of rapamycin inhibitor. Patients and methods: Fifty-seven patients with advanced solid tumors received BGT226 2.5-125 mg/day three times weekly (TIW). Dose escalation was guided by an adaptive Bayesian logistic regression model with overdose control. Assessments included response per RECIST, [18F]-fluorodeoxyglucose uptake, and phosphorylated-S6 in skin and paired tumor samples. Results: Three patients (125 mg cohort) had dose-limiting toxic effects (grade 3 nausea/vomiting, diarrhea). BGT226-related adverse events included nausea (68%), diarrhea (61%), vomiting (49%), and fatigue (19%). BGT226 demonstrated rapid absorption, variable systemic exposure, and a median half-life of 6-9 h. Seventeen patients (30%) had stable disease (SD) as best response. Nine patients had SD for ≥16 weeks. Thirty patients (53%) achieved stable metabolic disease as assessed by [18F]-fluorodeoxyglucose-positron emission tomography; however, no correlation between metabolic response and tumor shrinkage according to computed tomography was observed. PD changes suggested PI3K pathway inhibition but were inconsistent. Conclusions: The MTD of BGT226 was 125 mg/day TIW, and the clinically recommended dose was 100 mg/day TIW. Limited preliminary antitumor activity and inconsistent target inhibition were observed, potentially due to low systemic exposure.
Synergistic anti-tumor effects of a novel phosphatidyl inositol-3 kinase/mammalian target of rapamycin dual inhibitor BGT226 and gefitinib in non-small cell lung cancer cell lines
Cancer Lett 2014 Jun 1;347(2):196-203.PMID:24614285DOI:10.1016/j.canlet.2014.02.025.
Epidermal growth factor receptor (EGFR) and PI3K/mTOR pathway are drug targets for non-small cell lung cancer (NSCLC). Herein, we investigated anti-tumor effects of the combination of BGT226, a novel PI3K/mTOR dual inhibitor, and gefitinib on NSCLC cell lines which are high sensitive to gefitinib. The combination of BGT226 and gefitinib exhibited supra-additive growth inhibitory effects in PC-9 and HCC827 cells. Apoptotic induction and the inhibition of PI3K/mTOR signaling were enhanced by the combination. Significant tumor growth suppression was observed in xenograft model by the combination. These results suggest that the combination is effective in EGFR inhibitor-sensitive NSCLC therapy.