Alpelisib (formerly also known as BLY719; trade name: Piqray) is a novel, potent, newly approved, orally bioavailable phosphatidylinositol 3-kinase (PI3K) inhibitor with antineoplastic activity. As of May 2019, it has been approved by FDA as the first PI3K inhibitor to treat postmenopausal women, and men, with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, PIK3CA-mutated, advanced or metastatic breast cancer (as detected by an FDA-approved test) following progression on or after an endocrine-based regimen. PI3K inhibitor BYL719 specifically inhibits PIK3 in the PI3K/AKT kinase (or protein kinase B) signaling pathway, thereby inhibiting the activation of the PI3K signaling pathway. This may result in inhibition of tumor cell growth and survival in susceptible tumor cell populations. Activation of the PI3K signaling pathway is frequently associated with tumorigenesis. Dysregulated PI3K signaling may contribute to tumor resistance to a variety of antineoplastic agents. Clinical data suggests a disable safety profile with manageable side effects for BYL719.
理化性质和储存条件
| Molecular Weight (MW) | 441.47 |
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| Formula | C19H22F3N5O2S |
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| CAS No. | 1217486-61-7 |
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| Storage | -20℃ for 3 years in powder form |
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| -80℃ for 2 years in solvent |
| Solubility (In vitro) | DMSO: 88 mg/mL (199.33 mM) |
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| Water: 2 mg/mL (4.53 mM) |
| Ethanol: <1 mg/mL |
| Solubility (In vivo) | 30% PEG400+0.5% Tween80+5% Propylene glycol: 30 mg/mL |
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| Synonym/Chemical Name | Alpelisib; BYL719; BYL-719; BYL 719; NVP-BYL719; NVP BYL719; NVP-BYL-719; trade name: Piqray; (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 |
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实验参考方法
| In Vitro | Kinase Assay: Alpelisib (NVP-BYL719) potently inhibits the 2 most common PIK3CA somatic mutations (H1047R, E545K; IC50~4 nM). Alpelisib (NVP-BYL719) potently inhibits Akt phosphorylation in cells transformed with PI3Kα (IC50=74±15 nM) and shows significant reduced inhibitory activity in PI3Kβ or PI3Kδ isoforms transformed cells (≥15-fold compared with PI3Kα).
Cell Assay: Multiple myeloma cells (OPM1, OPM2, RPMI8226, U266, MM1s,MM1R) and NCI-H9290. BYL719 prominently decreases the activation of the PI3K signaling proteins (pAKT, pS6R, and pGSK), this effect are also observed in slico that BYL719 decreases the expression of the PI3K signaling proteins in a dose-dependent manner. Furthermore, BYL719 dose-dependently triggers G1 arrest and induces apoptosis in MM cells. BYL719 inhibits the proliferation of breast cancer cell lines harboring PIK3CA mutations, correlating with inhibition of various downstream signaling components of the PI3K/Akt pathway. |
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| In Vivo | BYL719(>270 mg/d) shows statistically significant dose-dependent anti-tumor efficacy in PIK3CA mutant xenograft models in rodents. BYL719 has a low clearance, a half-life of 8.5 h and its exposure increases dose proportionally between 30mg/d and 450mg/d, displaying a low inter-individual variability in Cmax and AUC in human. BYL719(270mg/d) shows first signs of clinical efficacy include 1 confirmed partial response in a patient with ER+ breast cancer, and significant PET responses (PMR) and/or tumor shrinkage are achieved in 8 out of 17 evaluated patients. |
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| Animal model | 5-week-old male C57Bl/6J mice transplanted with human osteoblastic osteosarcoma |
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| Formulation & Dosage | 12.5-50mg/kg; Oral gavage |
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| References | Br J Haematol. 2014 Apr;165(1):89-101. |
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