BYL-719 |
| (Synonyms: BYL 719; BYL719) Catalog No.: GC16462 |
BYL-719 (BYL-719) is a potent, selective, and orally active PI3Kα inhibitor. BYL-719 (BYL-719) shows efficacy in targeting PIK3CA-mutated cancer. BYL-719 (BYL-719) also inhibits p110α/p110γ/p110δ/p110β with IC50s of 5/250/290/1200 nM, respectively. Antineoplastic activity.
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Cas No.:1217486-61-7
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
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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, Muñoz-Martin M, et al. PI3Kα inhibition reduces obesity in mice. Aging (Albany NY). 2016 Nov 4;8(11):2747-2753.
| Cas No. | 1217486-61-7 | SDF | |
| Synonyms | BYL 719; BYL719 | ||
| Chemical Name | (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 | ||
| Formula | C19H22F3N5O2S | M.Wt | 441.47 |
| Solubility | ≥ 22.1mg/mL in DMSO | Storage | Store at -20°C |
| General tips | For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months. | ||
| Shipping Condition | Evaluation sample solution : ship with blue ice All other available size: ship with RT , or blue ice upon request |
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Combined Treatment with PI3K Inhibitors BYL-719 and CAL-101 Is a Promising Antiproliferative Strategy in Human Rhabdomyosarcoma Cells
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.
Regulation of PTEN translation by PI3K signaling maintains pathway homeostasis
The PI3K pathway regulates cell metabolism, proliferation, and migration, and its dysregulation is common in cancer. We now show that both physiologic and oncogenic activation of PI3K signaling increase the expression of its negative regulator PTEN. This limits the duration of the signal and output of the pathway. Physiologic and pharmacologic inhibition of the pathway reduces PTEN and contributes to the rebound in pathway activity in tumors treated with PI3K inhibitors and limits their efficacy. Regulation of PTEN is due to mTOR/4E-BP1-dependent control of its translation and is lost when 4E-BP1 is deleted. Translational regulation of PTEN is therefore a major homeostatic regulator of physiologic PI3K signaling and plays a role in reducing the pathway activation by oncogenic PIK3CA mutants and the antitumor activity of PI3K pathway inhibitors. However, pathway output is hyperactivated in tumor cells with coexistent PI3K mutation and loss of PTEN function.
KRAS inhibitors: going noncovalent
KRASG12D is the most frequent KRAS mutation in human cancer with particularly high frequencies in pancreatic and colorectal cancer. Informed by the structure of the KRASG12C inhibitor adagrasib, Hallin et al. have now, through multiple rounds of structure-based drug design, identified and validated a potent, selective, and noncovalent KRASG12D inhibitor, MRTX1133. This study demonstrated that MRTX1133 inhibited both the inactive and active state of KRASG12D and showed potent antitumor activity in several preclinical models of pancreatic and colorectal cancer, especially when combined with cetuximab, a monoclonal antibody against the EGFR, or BYL-719, a potent PI3Kα inhibitor.
Phase I study of alpelisib (BYL-719) and trastuzumab emtansine (T-DM1) in HER2-positive metastatic breast cancer (MBC) after trastuzumab and taxane therapy
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.
Alpelisib
No information is available on alpelisib during breastfeeding. The manufacturer recommends that breastfeeding be discontinued during alpelisib therapy and for 1 week after the final dose.
Average Rating: 5 (Based on Reviews and 32 reference(s) in Google Scholar.)
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