Class IA phosphoinositide 3-kinase (Class IA PI3K)

Class IA phosphoinositide 3-kinases (PI3Ks) are a family of heterodimeric lipid kinases that play a central role in regulating cell growth, proliferation, survival, and metabolism [1, 5, 14]. They consist of a p110 catalytic subunit (alpha, beta, or delta) and a p85-type regulatory subunit, and are primarily activated by receptor tyrosine kinases (RTKs) and small GTPases like Ras [1, 12, 13]. Upon activation, Class IA PI3Ks phosphorylate phosphatidylinositol 4,5-bisphosphate (PIP2) to generate the second messenger phosphatidylinositol 3,4,5-trisphosphate (PIP3), which recruits and activates downstream effectors such as AKT and mTOR [2, 11, 18]. Dysregulation of this pathway, often through activating mutations in the PIK3CA gene or loss of the tumor suppressor PTEN, is a hallmark of many human cancers, including breast, endometrial, and colorectal cancers [2, 7, 8]. Consequently, Class IA PI3Ks are major therapeutic targets, with several isoform-selective and pan-PI3K inhibitors approved for the treatment of various malignancies and rare genetic disorders like PIK3CA-related overgrowth spectrum (PROS) and activated PI3K delta syndrome (APDS) [17, 19]. However, therapeutic use is often limited by on-target toxicities such as hyperglycemia, gastrointestinal issues, and immune-mediated adverse effects [3, 6, 19].

Other names

PI3K class IAPhosphatidylinositol 3-kinase class IAClass IA PI 3-kinasep110/p85 complex

Inhibition of the catalytic activity of Class IA PI3K isoforms (p110α, p110β, and/or p110δ), preventing the phosphorylation of phosphatidylinositol 4,5-bisphosphate (PIP2) to phosphatidylinositol 3,4,5-trisphosphate (PIP3) and thereby suppressing the PI3K/AKT/mTOR signaling pathway [2, 11, 15].