Phosphoinositide-3-kinase alpha (PI3Kα)

Phosphoinositide-3-kinase alpha (PI3Kα) is a member of the Class I phosphoinositide 3-kinases, functioning as a lipid kinase that phosphorylates the 3′-hydroxyl group of phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3), a pivotal second messenger in cellular signaling pathways[2][3][7]. PI3Kα is a heterodimer, composed of a catalytic (p110α, encoded by PIK3CA) and a regulatory subunit (typically p85α), and is activated downstream of various receptor tyrosine kinases, integrating growth factor, hormonal, and oncogenic signals. The PI3K/AKT pathway orchestrates cell growth, proliferation, survival, metabolism, and motility, and its dysregulation, particularly via activating mutations in PIK3CA, is a driver of many cancers[2][3][7]. PI3Kα is an important drug target in oncology, with approved selective inhibitors such as alpelisib, and is being investigated for other indications including metabolic and inflammatory diseases. Inhibition of PI3Kα poses therapeutic challenges due to the enzyme's essential physiological roles, leading to potential toxicities, especially metabolic disturbances like hyperglycemia[4][7].

Other names

Phosphatidylinositol 3-kinase alphaPIK3CA (gene name)p110αPI3K-alphaClass I PI3K alpha

Inhibition of PI3Kα kinase activity (prevents production of PIP3 and downstream AKT activation); Allosteric activation (UCL-TRO-1938 enhances catalytic cycle); Blockade of oncogenic PIK3CA mutation signaling