Class I phosphoinositide 3-kinase catalytic subunit (Class I PI3K catalytic subunit) (Class I PI3K catalytic subunit)

Class I phosphoinositide 3-kinases (PI3Ks) are essential lipid kinases that function as key nodes in the PI3K/AKT/mTOR signaling pathway, regulating fundamental cellular processes such as growth, proliferation, and metabolism (Fruman et al., 2017, PMID: 28938118). These enzymes are heterodimers composed of a regulatory subunit and one of four catalytic p110 subunits: p110α (PIK3CA), p110β (PIK3CB), p110δ (PIK3CD), or p110γ (PIK3CG) (UniProt P42336, P42338, O00329, P48736). They catalyze the phosphorylation of phosphatidylinositol 4,5-bisphosphate (PIP2) to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3), a critical second messenger that recruits AKT to the plasma membrane for activation (Vanhaesebroeck et al., 2010, PMID: 20495598). Dysregulation of these catalytic subunits, through gain-of-function mutations (especially in PIK3CA) or loss of the negative regulator PTEN, is a hallmark of many human cancers and primary immunodeficiencies (PMID: 30635554). Consequently, these subunits are major therapeutic targets, with several isoform-selective and pan-PI3K inhibitors approved or in clinical development for treating malignancies and inflammatory conditions (FDA Label: Piqray, 2019; FDA Label: Zydelig, 2014). Therapeutic challenges include managing isoform-specific toxicities, such as hyperglycemia for α-inhibitors and immune-mediated colitis for δ-inhibitors.

Other names

p110 subunitPI3K catalytic subunitPhosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA)Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta (PIK3CB)Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta (PIK3CD)Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma (PIK3CG)

Class I PI3K inhibitors typically act as ATP-competitive inhibitors that bind to the ATP-binding pocket of the p110 catalytic subunit. This prevents the enzyme from phosphorylating phosphatidylinositol 4,5-bisphosphate (PIP2) into phosphatidylinositol 3,4,5-trisphosphate (PIP3), thereby blocking the recruitment of AKT and other pleckstrin homology (PH) domain-containing proteins to the plasma membrane, which effectively shuts down downstream signaling pathways involved in cell growth and survival (Fruman et al., 2017, PMID: 28938118; Vanhaesebroeck et al., 2010, PMID: 20495598).