BEZ235 (NVP-BEZ235)

NVP-BEZ235 is a novel therapeutic agent that targets 2 molecules in thePI3K/Akt/mTOR (phosphatidylinositol 3-kinase) pathway, PI3K and mTOR. It is an ATP-competitive pan-class I PI3K inhibitor that is effective against p110α with hotspot mutations, and likewise inhibits both mammalian target of rapamycin complex 1 (mTORC1) and mTORC2 ^[1]. NVP-BEZ235 antagonizes the PI3K/mTOR signaling pathway and induces cell-cycle arrest, autophagy, and downregulation of vascular endothelial growth factor in glioma cells. NVP-BEZ235 is also an effective radiosensitizer that inhibits ataxia telangiectasia mutated (ATM) and DNA-PK catalytic subunits (DNA-PKcs), arrests cell cycle, and induces apoptosis ^[2].

NVP-BEZ235 treated colorectal cancer (CRC) cell lines resulted in transient PI3K blockade, sustained decreases in mTORC1/mTORC2 signaling, and a corresponding decrease in cell viability (IC₅₀ = 9.0-14.3 nM) ^[3]. All cell lines with PI3K-activating mutations or Pten deletions (A2780, IGROV1, MOVCAR18, OAW42, and SKOV3) were highly sensitive to NVP-BEZ235 (IC₅₀ range 26-70 nM). In contrast, HEYC2, OV167, OV207, and OVCAR5 cells, that lack PI3K-activating mutations or Pten deletions, had an IC₅₀ ≥ 100 nM (IC₅₀ range 100-210 nM) for NVP-BEZ235. Overall, a statistically significant difference between the average NVP-BEZ235 IC₅₀ for cell lines with PI3K mutations or Pten deletions (IC₅₀ = 48.5 ± 8.1 nM) compared to cell lines that lack these mutations (IC₅₀ = 95.9 ± 18.4 nM) ^[1].

Mouse model of Alzheimer's disease (AD) that expresses a mutant amyloid-β precursor protein (T41 mice) to investigate the effects of NVP-BEZ235. Ten-months-old T41 animals were treated for 14 days with NVP-BEZ235 or vehicle via oral gavage and then submitted to social memory, open field and contextual conditioned fear tests. Hippocampal slices were prepared and Aβ1-42 content, NeuN, Iba-1, CD68 and GFAP were evaluated. Tissues were further processed to evaluate cytokines levels through cytometric bead array. The treatment with NVP-BEZ235 (5 mg/kg) reduced social memory impairment in T41 mice. The drug reduced the CD68/Iba-1 ratio in CA3 region of hippocampus. NVP-BEZ235 diminished IL-10 levels in T41 mice ^[4].

References:
[1]. C. Santiskulvong, G.E. Konecny, M. Fekete, et al. Dual targeting of phosphoinositide 3-kinase and mammalian target of rapamycin using NVP-BEZ235 as a novel therapeutic approach in human ovarian carcinoma. Clin. Cancer Res., 17 (2011), pp. 2373-2384
[2]: Wang WJ, Long LM, Yang N, et al. NVP-BEZ235, a novel dual PI3K/mTOR inhibitor, enhances the radiosensitivity of human glioma stem cells in vitro. Acta Pharmacol Sin. 2013;34:681-690.
[3]. J. Roper, M.P. Richardson, W.V. Wang, L.G. Richard, W. Chen, E.M. Coffee, et al. The dual PI3K/mTOR inhibitor NVP-BEZ235 induces tumor regression in a genetically engineered mouse model of PIK3CA wild-type colorectal cancer. PLoS ONE, 6 (2011), p. e25132
[4]. P.M.Q. Bellozi, G.F. Gomes, L.R. de Oliveira, et al. NVP-BEZ235 (Dactolisib) has protective effects in a transgenic mouse model of Alzheimer's disease. Frontiers in Pharmacology, 10 (2019), p. 1345

NVP-BEZ235 是一种新型治疗剂,靶向 PI3K/Akt/mTOR（磷脂酰肌醇 3-激酶）通路中的 2 个分子,即 PI3K 和 mTOR。它是一种 ATP 竞争性泛 I 类 PI3K 抑制剂,对具有热点突变的 p110α 有效,同样抑制哺乳动物雷帕霉素靶标复合物 1 (mTORC1) 和 mTORC2 ^[1]。 NVP-BEZ235 拮抗 PI3K/mTOR 信号通路并诱导细胞周期停滞、自噬和神经胶质瘤细胞中血管内皮生长因子的下调。 NVP-BEZ235 也是一种有效的放射增敏剂,可抑制共济失调性毛细血管扩张症突变 (ATM) 和 DNA-PK 催化亚基 (DNA-PKcs)、阻滞细胞周期并诱导细胞凋亡^[2]。

NVP-BEZ235 处理的结直肠癌 (CRC) 细胞系导致短暂的 PI3K 阻断、mTORC1/mTORC2 信号持续降低以及细胞活力相应降低（IC₅₀ = 9.0-14.3 nM ) ^[3]。所有具有 PI3K 激活突变或 Pten 缺失的细胞系（A2780、IGROV1、MOVCAR18、OAW42 和 SKOV3）对 NVP-BEZ235 高度敏感（IC₅₀ 范围 26-70 nM）。相反,缺乏 PI3K 激活突变或 Pten 缺失的 HEYC2、OV167、OV207 和 OVCAR5 细胞的 IC₅₀ ≥ 100 nM（IC₅₀ 范围为 100- 210 nM）对于 NVP-BEZ235。总体而言,与细胞系相比,具有 PI3K 突变或 Pten 缺失的细胞系的平均 NVP-BEZ235 IC₅₀（IC₅₀ = 48.5 ± 8.1 nM）之间存在统计学显着差异缺乏这些突变 (IC₅₀ = 95.9 ± 18.4 nM) ^[1]。

阿尔茨海默病 (AD) 小鼠模型表达了一种突变型淀粉样蛋白-β 前体蛋白（T41 小鼠）,以研究 NVP-BEZ235 的作用。 10 个月大的 T41 动物通过口服强饲法用 NVP-BEZ235 或载体治疗 14 天,然后进行社交记忆、开放场和情境条件恐惧测试。制备海马切片并评估Aβ1-42含量、NeuN、Iba-1、CD68和GFAP。进一步处理组织以通过细胞计数珠阵列评估细胞因子水平。用 NVP-BEZ235 (5 mg/kg) 治疗可减少 T41 小鼠的社交记忆障碍。该药降低了海马CA3区的CD68/Iba-1比值。 NVP-BEZ235 降低了 T41 小鼠的 IL-10 水平^[4]。