Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha (PI3Kα) (PI3Kα)

Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha (PI3Kα) is a critical lipid kinase involved in the PI3K/AKT/mTOR signaling pathway, which regulates cell growth, survival, and metabolism [UniProt: P42336]. Mutations in the PIK3CA gene, which encodes the p110α subunit, are highly prevalent in various cancers, including breast, colorectal, and endometrial cancers [PubMed: 25877202]. These mutations primarily occur in two "hotspots": the helical domain (e.g., E542K, E545K) and the kinase domain (e.g., H1047R), both of which result in gain-of-function and constitutive pathway activation [PubMed: 15016963]. Helical domain mutations typically function by disrupting the inhibitory contact with the p85 regulatory subunit, whereas kinase domain mutations increase the catalytic activity and membrane binding of the p110α subunit [PubMed: 19443738]. Targeted therapies like alpelisib (Piqray) and inavolisib have been developed to specifically inhibit PI3Kα, particularly in patients harboring these specific mutations [FDA, 2019]. However, because PI3Kα is essential for insulin signaling, inhibitors often cause systemic hyperglycemia as a primary side effect [PubMed: 31141654].

Other names

PIK3CAp110αPhosphoinositide-3-kinase catalytic alpha polypeptidePI3-kinase subunit alphaPI3Kα helical domain mutantsPI3Kα kinase domain mutants

ATP-competitive inhibition of the p110α catalytic subunit, preventing the conversion of phosphatidylinositol 4,5-bisphosphate (PIP2) to phosphatidylinositol 3,4,5-trisphosphate (PIP3), thereby blocking downstream AKT/mTOR signaling.