BYL-719
(Synonyms: 阿培利司,BYL 719; BYL719) 目录号 : GC16462
An inhibitor of PI3Kα
Cas No.:1217486-61-7
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >99.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
| Cell experiment [1]: | |
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Cell lines |
Rhabdomyosarcoma cell line（RD,SJCRH30 and A204) |
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Preparation Method |
BYL-719 was dissolved in DMSO,to generate a stock solution (10 mM) which was subsequently diluted with the medium before adding to the cells. Rhabdomyosarcoma cell line were treated with BYL-719, then cell viability was evaluated by MTT assay. |
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Reaction Conditions |
Rhabdomyosarcoma cell line were treated with BYL-719 (0-20μM) for 72 h. |
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Applications |
BYL-719 decrease the viability of rhabdomyosarcoma(RMS) cell lines.BYL-719 treatment significantly affected cell proliferation of all the Rhabdomyosarcoma cell lines tested, confirming that PI3Kɑ was one of the isoforms expected to be involved in sustaining RMS cell proliferation. |
| Animal experiment [2]: | |
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Animal models |
Wild-type FVB/N mice, c-Met/H1047R mice |
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Preparation Method |
BYL-719 was administered daily by oral gavage.Treatments were performed for 3 consecutive weeks after moderate tumor burden occurred. |
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Dosage form |
25mg/kg/day, oral gavage |
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Applications |
BYL-719 suppressed HCC angiogenesis in all the mouse models tested. BYL-719-treated mice were alive and in relatively good conditions when harvested after 3 weeks of treatment.Lliver weight in the BYL-719 cohort was lower than that from the vehicle cohort and similar to that of pretreatment tumor burden. |
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References: [1]. Piazzi M, Bavelloni A, et al. Combined Treatment with PI3K Inhibitors BYL-719 and CAL-101 Is a Promising Antiproliferative Strategy in Human Rhabdomyosarcoma Cells. Molecules. 2022 Apr 24;27(9):2742. [2]. Xu H, Chen K, et al. Alpelisib combination treatment as novel targeted therapy against hepatocellular carcinoma. Cell Death Dis. 2021 Oct 8;12(10):920. |
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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]。
| Cas No. | 1217486-61-7 | SDF | |
| 别名 | 阿培利司,BYL 719; BYL719 | ||
| 化学名 | (2S)-1-N-[4-methyl-5-[2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl]-1,3-thiazol-2-yl]pyrrolidine-1,2-dicarboxamide | ||
| Canonical SMILES | CC1=C(SC(=N1)NC(=O)N2CCCC2C(=O)N)C3=CC(=NC=C3)C(C)(C)C(F)(F)F | ||
| 分子式 | C19H22F3N5O2S | 分子量 | 441.47 |
| 溶解度 | ≥ 22.1mg/mL 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 | 2.2652 mL | 11.3258 mL | 22.6516 mL |
| 5 mM | 0.453 mL | 2.2652 mL | 4.5303 mL |
| 10 mM | 0.2265 mL | 1.1326 mL | 2.2652 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 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 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
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.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Combined Treatment with PI3K Inhibitors BYL-719 and CAL-101 Is a Promising Antiproliferative Strategy in Human Rhabdomyosarcoma Cells
Molecules2022 Apr 24;27(9):2742.PMID: 35566091DOI: 10.3390/molecules27092742
Rhabdomyosarcoma (RMS) is a highly malignant and metastatic pediatric cancer arising from skeletal muscle myogenic progenitors. Recent studies have shown an important role for AKT signaling in RMS progression. Aberrant activation of the PI3K/AKT axis is one of the most frequent events occurring in human cancers and serves to disconnect the control of cell growth, survival, and metabolism from exogenous growth stimuli. In the study reported here, a panel of five compounds targeting the catalytic subunits of the four class I PI3K isoforms (p110α, BYL-719 inhibitor; p110β, TGX-221 inhibitor; p110γ, CZC24832; p110δ, CAL-101 inhibitor) and the dual p110α/p110δ, AZD8835 inhibitor, were tested on the RMS cell lines RD, A204, and SJCRH30. Cytotoxicity, cell cycle, apoptosis, and the activation of downstream targets were analyzed. Of the individual inhibitors, BYL-719 demonstrated the most anti-tumorgenic properties. BYL-719 treatment resulted in G1/G0 phase cell cycle arrest and apoptosis. When combined with CAL-101, BYL-719 decreased cell viability and induced apoptosis in a synergistic manner, equaling or surpassing results achieved with AZD8835. In conclusion, our findings indicate that BYL-719, either alone or in combination with the p110δ inhibitor, CAL-101, could represent an efficient treatment for human rhabdomyosarcoma presenting with aberrant upregulation of the PI3K signaling pathway.
Phase I study of alpelisib (BYL-719) and trastuzumab emtansine (T-DM1) in HER2-positive metastatic breast cancer (MBC) after trastuzumab and taxane therapy
Breast Cancer Res Treat2018 Sep;171(2):371-381.PMID: 29850984DOI: 10.1007/s10549-018-4792-0
Purpose: Activation of the phosphoinositide 3-kinase (PI3K) pathway is an important resistance mechanism to anti-HER2 therapies. This study aimed to assess the safety and activity of alpelisib (a PI3Kα isoform-specific inhibitor) with T-DM1 in trastuzumab- and taxane-resistant HER2-positive MBC.
Methods: Patients with HER2-positive MBC that had progressed on trastuzumab-based therapy were treated with alpelisib daily and T-DM1 3.6 mg/kg every 3 weeks. The dose-limiting toxicity (DLT), maximum tolerated dose (MTD), adverse events, overall response rate (ORR), and clinical benefit rate (CBR = CR + PR + SD > 6 months) were assessed with descriptive statistics. Progression-free survival (PFS) was calculated by the Kaplan-Meier method.
Results: Seventeen patients were enrolled with a median of 3 prior therapies for metastatic disease. The DLT was a maculopapular rash and MTD was 250 mg alpelisib daily. The most frequently occurring toxicities included fatigue, rash, gastrointestinal side effects, thrombocytopenia, anemia, elevated liver enzymes, and hyperglycemia. Fourteen patients were evaluable for response with an ORR of 43%. In patients with prior treatment and progression on T-DM1 (n = 10), the ORR was 30%. The CBR was 71% in evaluable patients and 60% in those with prior T-DM1. The median PFS was 8.1 months.
Conclusions: The combination of alpelisib and T-DM1 is tolerable and demonstrates activity in trastuzumab-resistant HER2-positive MBC. Furthermore, activity was observed in T-DM1-resistant disease. These data suggest that PIK3CA inhibition targets an important resistance pathway to anti-HER2 therapy, providing rationale for further study of PI3K inhibition in refractory HER2-positive MBC to validate these results.
Cryo-EM structures of PI3Kα reveal conformational changes during inhibition and activation
Proc Natl Acad Sci U S A2021 Nov 9;118(45):e2109327118.PMID: 34725156DOI: 10.1073/pnas.2109327118
Phosphoinositide 3-kinases (PI3Ks) are lipid kinases essential for growth and metabolism. Their aberrant activation is associated with many types of cancers. Here we used single-particle cryoelectron microscopy (cryo-EM) to determine three distinct conformations of full-length PI3Kα (p110α-p85α): the unliganded heterodimer PI3Kα, PI3Kα bound to the p110α-specific inhibitor BYL-719, and PI3Kα exposed to an activating phosphopeptide. The cryo-EM structures of unbound and of BYL-719-bound PI3Kα are in general accord with published crystal structures. Local deviations are presented and discussed. BYL-719 stabilizes the structure of PI3Kα, but three regions of low-resolution extra density remain and are provisionally assigned to the cSH2, BH, and SH3 domains of p85. One of the extra density regions is in contact with the kinase domain blocking access to the catalytic site. This conformational change indicates that the effects of BYL-719 on PI3Kα activity extend beyond competition with adenosine triphosphate (ATP). In unliganded PI3Kα, the DFG motif occurs in the "in" and "out" positions. In BYL-719-bound PI3Kα, only the DFG-in position, corresponding to the active conformation of the kinase, was observed. The phosphopeptide-bound structure of PI3Kα is composed of a stable core resolved at 3.8 Å. It contains all p110α domains except the adaptor-binding domain (ABD). The p85α domains, linked to the core through the ABD, are no longer resolved, implying that the phosphopeptide activates PI3Kα by fully releasing the niSH2 domain from binding to p110α. The structures presented here show the basal form of the full-length PI3Kα dimer and document conformational changes related to the activated and inhibited states.
Effects of PI3K inhibition in AI-resistant breast cancer cell lines: autophagy, apoptosis, and cell cycle progression
Breast Cancer Res Treat2021 Nov;190(2):227-240.PMID: 34498152DOI: 10.1007/s10549-021-06376-4
Introduction: Breast cancer is the leading cause of cancer death in women. The aromatase inhibitors (AIs), Anastrozole (Ana), Letrozole (Let), and Exemestane (Exe) are a first-line treatment option for estrogen receptor-positive (ER+) breast tumors, in postmenopausal women. Nevertheless, the development of acquired resistance to this therapy is a major drawback. The involvement of PI3K in resistance, through activation of the PI3K/AKT/mTOR survival pathway or through a cytoprotective autophagic process, is widely described.
Materials and methods: The involvement of autophagy in response to Ana and Let treatments and the effects of the combination of BYL-719, a PI3K inhibitor, with AIs were explored in AI-resistant breast cancer cell lines (LTEDaro, AnaR, LetR, and ExeR).
Results: We demonstrate that Ana and Let treatments do not promote autophagy in resistant breast cancer cells, contrary to Exe. Moreover, the combinations of BYL-719 with AIs decrease cell viability by different mechanisms by nonsteroidal vs. steroidal AIs. The combination of BYL-719 with Ana or Let induced cell cycle arrest while the combination with Exe promoted cell cycle arrest and apoptosis. In addition, BYL-719 decreased AnaR, LetR, and ExeR cell viability in a dose- and time-dependent manner, being more effective in the ExeR cell line. This decrease was further exacerbated by ICI 182,780.
Conclusion: These results corroborate the lack of cross-resistance between AIs verified in the clinic, excluding autophagy as a mechanism of resistance to Ana or Let and supporting the ongoing clinical trials combining BYL-719 with AIs.