Alpelisib 是一种选择性的，有效的，具有口服活性的PI3Kα抑制剂，具有抗肿瘤活性。它对 PIK3CA 突变癌具有靶向性。它抑制 p110α (IC50:5 nM)、p110γ (IC50:250 nM)、p110δ (IC50:290 nM)、p110β (IC50:1200 nM)。

Alpelisib is an orally bioavailable PI3Kα inhibitor (IC50: 5 nM in a cell-free assay) with potential antineoplastic activity and minimal effect on PI3Kβ/γ/δ.

In biochemical assays, Alpelisib (NVP-BYL719) inhibits wild-type PI3Kα (IC50: 4.6 nmol/L) more potently than the PI3Kδ (IC50: 290 nmol/L) and PI3Kγ (IC50: 250 nmol/L) isoforms and shows significantly reduced activity against PI3Kβ (IC50: 1,156 nmol/L). Here, in addition, we show that NVP-BYL719 potently inhibits the 2 most common PIK3CA somatic mutations (H1047R, E545K; IC50～4 nmol/L). NVP-BYL719 potently inhibited Akt phosphorylation in cells transformed with PI3Kα (IC50: 74 ± 15 nmol/L) and showed significantly reduced inhibitory activity in PI3Kβ or PI3Kδ isoforms transformed cells (≥15-fold compared with PI3Kα) [1]. After 72 hr of treatment, BYL719 significantly inhibited the cell growth of all osteosarcoma cell lines tested in a dose-dependent manner with an IC50 ranging from 6 to 15 mM and with the IC90 from 24 to 42 mM at 72 hr [2].

NVP-BYL719 (12.5, 25, or 50 mg/kg, p.o.) treatment was associated with dose and time-dependent inhibition of the PI3K/Akt pathway, which notably paralleled time-dependent drug exposure in tumor and plasma. Rat1-myr-p110α tumor-bearing nude mice were treated orally every day with the compound for up to 8 consecutive days. Treatments of 12.5, 25, and 50 mg/kg were well tolerated and resulted in a dose-dependent and statistically significant antitumor effect [1]. BYL719 significantly reduced tumor volumes in a dose-dependent manner compared to a vehicle group (p< 0.01 and p< 0.001, respectively for 12.5 and 50 mg/kg BYL719) [2].

To evaluate the isoform-specific potency of NVP-BYL719 in a cell-based system, an N-terminally myristoylated form of each PI3K class IA isoform was expressed in Rat1 fibroblasts. The retroviral expression plasmid pBabePuro containing human p110α, p110β, and p110δ with an N-terminal myristoylation (myr) signal followed by an HA-tag were generated. Successfully infected Rat1 cells were selected in medium containing 4 μg/mL of puromycin, expanded and characterized for expression of the p110 isoforms. Transgenic expression of the myristoylated protein was confirmed by increased levels of phosphorylated Akt [1].

All in life experimentation and efficacy studies were conducted as described previously. Tumor xenografts were grown subcutaneously or orthotopically in nude mice or nude Rowett rats (Hsd: RH-Fox1rnu) by injection of 3 × 10^6 to 1 × 10^7 cells or implantation of tumor fragments of approximately 50 mg. Tumor-bearing animals mice were treated with either vehicle control, NVP-BYL719, or NVP-BKM120 (p.o., every day) at the doses indicated [1].

1217486-61-7

C19H22F3N5O2S

441.47

BYL-719

DMSO:82 mg/mL (185.7 mM)
Ethanol:2 mg/mL (4.53 mM)
Powder: -20°C for 3 years
In solvent: -80°C for 2 years