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;Alpelisib

[1]Elkabets M, et al. mTORC1 inhibition is required for sensitivity to PI3K p110α inhibitors in PIK3CA-mutant breast cancer. Sci Transl Med. 2013 Jul 31;5(196):196ra99. [2]Yang T, Xu R, Su Q, et al. Chelerythrine hydrochloride inhibits proliferation and induces mitochondrial apoptosis in cervical cancer cells via PI3K/BAD signaling pathway[J]. Toxicology in Vitro. 2020, 68: 104965. [3]Fritsch C, et al. Characterization of the novel and specific PI3Kα inhibitor NVP-BYL719 and development of the patient stratification strategy for clinical trials. Mol Cancer Ther. 2014 May;13(5):1117-29. [4]Liao W, Wang Z, Han Y, et al. Design, synthesis and biological activity of novel 2, 3, 4, 5-tetra-substituted thiophene derivatives as PI3Kα inhibitors with potent antitumor activity[J]. European Journal of Medicinal Chemistry. 2020: 112309. [5]Young CD, et al. Conditional loss of ErbB3 delays mammary gland hyperplasia induced by mutant PIK3CA without affecting mammary tumor latency, gene expression, or signaling. Cancer Res. 2013 Jul 1;73(13):4075-85. [6]Gobin B, et al. BYL719, a new α-specific PI3K inhibitor: single administration and in combination with conventional chemotherapy for the treatment of osteosarcoma. Int J Cancer. 2015 Feb 15;136(4):784-96.

[1]Liao W, Wang Z, Han Y, et al. Design, synthesis and biological activity of novel 2,3,4,5-tetra-substituted thiophene derivatives as PI3Kα inhibitors with potent antitumor activity. European Journal of Medicinal Chemistry. 2020, 197: 112309 [2]Yang T, Xu R, Su Q, et al. Chelerythrine hydrochloride inhibits proliferation and induces mitochondrial apoptosis in cervical cancer cells via PI3K/BAD signaling pathway. Toxicology in Vitro. 2020, 68: 104965.

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