BYL-719

BYL719 (Alpelisib) is a selective PI3Kɑ inhibitor.It induced fewer toxicities and had a more favorable safety profile compared to a pan class I PI3K inhibitor.PI3K/AKT and mTOR pathways regulate several processes involved in cell survival, protein synthesis, cell proliferation and differentiation, metabolism, senescence, motility, and angiogenesis.Results from preclinical studies show that BYL719 inhibits PI3K signaling and prevents AKT phosphorylation in cell lines harboring?PIK3CA?mutations, and blocks tumor growth in xenograft models^[1].

BYL-719 treatment induced G0/G1 cell cycle arrest irrespective of PIK3CA mutational status. Notably, in PIK3CA-mutant cells (AGS and MKN1), sub-G1 fraction remarkably increased (p?<?0.05), suggesting increased apoptosis by BYL-719 in these cell lines. BYL-719 in combination with paclitaxel demonstrated synergistic anti-proliferative effects, preferentially in PIK3CA-mutant GC cells, resulting in increased DNA damage response and apoptosis^[2].

In mouse xenograft model of PIK3CA-mutant MKN1 GC cells, BYL-719 (25mg/kg/day) combined with paclitaxel (20mg/kg/day) significantly enhanced anti-tumor activity by decreasing Ki-67 expression and increasing TUNEL expression. Moreover, this combination prolonged the survival of tumor-bearing mice during 4 weeks of treatment period without resulting in significant change in body weight^[2].

Oral consumption of BYL-719 results in dose-dependent hyperglycemia and hyperinsulinemia. Littermates were block-randomised to receive either the diet containing either 0.3 g/kg BYL-719. Following 6 weeks of treatment higher fed blood glucose and plasma insulin levels were evident in the BYL-719 treated groups, and a trend towards decreased body weight was seen with BYL-719 treatment without a difference in food intake. We have previously shown that p110α inhibitors can prevent weight gain in young (4–5 weeks old) mice during development^[3].

BYL-719 reduces obesity and elevates energy expenditure in mice.The most dramatic on-target effect of BYL-719 was hyperglycemia, which in the case of the ob/ob mice was severe due to their diabetic condition.However, it is important to note that in normal lean mice, the glycemia induced by PI3Kɑ inhibition is within physiological range ^[4].

References:
[1].Ando Y, Iwasa S, et al. Phase I study of alpelisib (BYL719), an α-specific PI3K inhibitor, in Japanese patients with advanced solid tumors. Cancer Sci. 2019 Mar;110(3):1021-1031.
[2].Kim KJ, Kim JW, et al. PI3K-targeting strategy using alpelisib to enhance the antitumor effect of paclitaxel in human gastric cancer. Sci Rep. 2020 Jul 23;10(1):12308.
[3].Hedges CP, Pham T, et al. Prolonged treatment with a PI3K p110α inhibitor causes sex- and tissue-dependent changes in antioxidant content, but does not affect mitochondrial function. Biosci Rep. 2020 Oct 30;40(10):BSR20201128.
[4].Lopez-Guadamillas E, Mu?oz-Martin M, et al. PI3Kα inhibition reduces obesity in mice. Aging (Albany NY). 2016 Nov 4;8(11):2747-2753.

BYL719 (Alpelisib) 是一种选择性 PI3Kɑ 抑制剂。与泛 I 类 PI3K 抑制剂相比，它引起的毒性更少，安全性更佳。PI3K/AKT 和 mTOR 通路调节涉及细胞存活、蛋白质合成、细胞增殖和分化、代谢、衰老、运动和血管生成。临床前研究结果表明，BYL719 在携带 PIK3CA 突变的细胞系中抑制 PI3K 信号并阻止 AKT 磷酸化，并在异种移植模型中阻断肿瘤生长^[1].

BYL-719 处理诱导 G0/G1 细胞周期停滞，与 PIK3CA 突变状态无关。值得注意的是，在 PIK3CA 突变细胞（AGS 和 MKN1）中，亚 G1 部分显着增加（p><>0.05），表明 BYL-719 在这些细胞系中增加了细胞凋亡。 BYL-719 联合紫杉醇显示出协同抗增殖作用，优先作用于 PIK3CA 突变型 GC 细胞，导致 DNA 损伤反应和细胞凋亡增加^[2]。

在 PIK3CA 突变体 MKN1 GC 细胞的小鼠异种移植模型中，BYL-719（25mg/kg/天）联合紫杉醇（20mg/kg/天）通过降低 Ki-67 表达和增加 TUNEL 显着增强抗肿瘤活性表达。此外，这种组合在 4 周的治疗期间延长了荷瘤小鼠的存活时间，而没有导致体重显着变化^[2]。

口服 BYL-719 会导致剂量依赖性高血糖和高胰岛素血症。同窝仔仔被分组随机接受含有 0.3 g/kg BYL-719 的饮食。治疗 6 周后，BYL-719 治疗组的进食血糖和血浆胰岛素水平明显升高，并且在 BYL-719 治疗组中观察到体重下降的趋势，而食物摄入量没有差异。我们之前已经表明，p110α 抑制剂可以防止幼鼠（4-5 周大）在发育过程中体重增加^[3]。

BYL-719 减少了小鼠的肥胖并增加了能量消耗。BYL-719 最显着的靶向作用是高血糖，在 ob/ob 小鼠的情况下，由于其糖尿病状况，这种情况很严重。然而，它需要注意的是，在正常瘦小鼠中，PI3Kɑ 抑制诱导的血糖在生理范围内^[4]。

BYL719 (Alpelisib) 是一种选择性 PI3Kɑ 抑制剂。