Phosphatidylinositol-3-kinases (PI3Ks) are a family of important lipid kinases. PI3Ks are important in controlling the signaling pathways involved in cell proliferation, motility, cell death, and cell invasion. Moreover, PI3Ks control and deliver cellular signals in the PI3K/Akt/mTOR pathway by phosphorylating phosphatidylinositol 4,5-bisphosphate (PIP2) to phosphatidylinositol 3,4,5-trisphosphate (PIP3) on the membrane. PI3Ks consist of three classes, with different sequences, expressing tissues, substrate preferences, and functions.

PI3Kα is a therapeutic target of high interest in anticancer drug research. PI3Ka is the only Class I PI3K that has frequent oncogenic mutations in cancer. In particular, PI3Kα is an obligate heterodimer, which includes the p85α regulatory subunit and p110a catalytic subunit. PI3Kα is a principal Ras effector that phosphorylates PIP2 to PIP3 in the PI3K/Akt/mTOR pathway. Alpelisib (NVP-BYL719) is a potent α-specific PI3K inhibitor

In biochemical assays Alpelisib inhibits wild-type PI3Kα (IC₅₀=4.6 nM) more potently than the PI3Kδ (IC₅₀=290 nM and PI3Kγ (IC₅₀= 250 nM) isoforms. Especially, Alpelisib shows significantly reduced activity against PI3Kβ (IC₅₀=1,156 nM). In addition, Alpelisib potently inhibits the 2 most common PIK3CA somatic mutations (H1047R, E545K; IC₅₀∼4 nM). Alpelisib potently inhibits Akt phosphorylation in cells transformed with PI3Kα (IC₅₀=74 nM). Furthermore, Alpelisib shows significant reduced inhibitory activity in PI3Kβ or PI3Kδ isoforms transformed cells. Alpelisib has shown good efficacy in inhibiting the growth of PI3Kα driven tumors in animal xenograft models as well as good tolerability.

In summary, Alpelisib is a potent and selective PI3Ka inhibitor having a suitable absorption distribution metabolism excretion (ADME) profile for pharmacological evaluation.