Phosphatidylinositol 4,5-bisphosphate 3-kinase, class I (PI3K class I)

Phosphatidylinositol 4,5-bisphosphate 3-kinase, class I (PI3K class I) is a family of lipid kinases that function as critical mediators in the PI3K/AKT/mTOR signaling pathway (Guide to Pharmacology, 2025). These enzymes catalyze the phosphorylation of phosphatidylinositol 4,5-bisphosphate (PIP2) to generate the second messenger phosphatidylinositol 3,4,5-trisphosphate (PIP3) at the plasma membrane (UniProt, 2024). Class I PI3Ks consist of four catalytic isoforms—p110α, p110β, p110δ, and p110γ—which are activated by upstream signals from receptor tyrosine kinases and G protein-coupled receptors (NIH, 2023). The production of PIP3 recruits pleckstrin homology (PH) domain-containing proteins, such as AKT and PDK1, to regulate cell growth, survival, proliferation, and metabolism (Wikipedia, 2024). Hyperactivation of this pathway is a hallmark of many human cancers, frequently driven by gain-of-function mutations in the PIK3CA gene or loss of the tumor suppressor PTEN (NIH, 2023). Consequently, PI3K class I has become a major therapeutic target, with several isoform-specific and pan-PI3K inhibitors approved for treating breast cancer and various hematologic malignancies (NIH, 2023). However, the clinical utility of these drugs is often challenged by significant on-target toxicities, including hyperglycemia, gastrointestinal issues, and immune-mediated adverse effects (NIH, 2023).

Other names

PI3-kinase class IPhosphoinositide 3-kinase class IClass I PI3Kp110 alpha/beta/delta/gammaPI3K alpha/beta/delta/gamma

Inhibition of the catalytic activity of Class I PI3K isoforms (p110α, p110β, p110δ, p110γ), preventing the phosphorylation of phosphatidylinositol 4,5-bisphosphate (PIP2) to phosphatidylinositol 3,4,5-trisphosphate (PIP3), thereby blocking the recruitment of PH-domain containing proteins like AKT and PDK1 and inhibiting the PI3K/AKT/mTOR signaling pathway (NIH, 2023; Guide to Pharmacology, 2025).