Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform (p110α) (p110α)

The PI3Kα p110α catalytic subunit, encoded by the PIK3CA gene, is a critical component of the Class IA phosphoinositide 3-kinase (PI3K) complex, which functions as a lipid kinase [1, 2]. It plays a central role in the PI3K/AKT/mTOR signaling pathway by phosphorylating PIP2 to generate the second messenger PIP3, thereby regulating essential cellular processes such as growth, proliferation, survival, and glucose metabolism [3, 5]. Mutations in the PIK3CA gene, particularly hotspot mutations like H1047R and E545K, lead to constitutive activation of the enzyme and are among the most frequent genetic alterations in human cancers, including breast, colorectal, and endometrial carcinomas [1, 4]. Beyond its role in oncology, germline or mosaic mutations in p110α are associated with PIK3CA-related overgrowth spectrum (PROS) and other developmental disorders [3, 4]. Therapeutic strategies focus on ATP-competitive inhibitors, such as alpelisib and inavolisib, which are designed to selectively target the alpha isoform to minimize off-target toxicities [2, 5]. However, because p110α is the primary mediator of insulin signaling, its inhibition frequently results in systemic side effects like hyperglycemia and rash [1, 5].

Other names

PIK3CAp110-alphaPI3K-alphaPhosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alphaMCMMCAPCLOVECWS5CLAPOCCM4

Drugs targeting the PI3Kα p110α catalytic subunit typically act as ATP-competitive inhibitors. By binding to the ATP-binding pocket of the p110α subunit, these agents prevent the phosphorylation of phosphatidylinositol 4,5-bisphosphate (PIP2) into phosphatidylinositol 3,4,5-trisphosphate (PIP3). This inhibition disrupts the recruitment of PH-domain-containing proteins like AKT to the plasma membrane, thereby suppressing the PI3K/AKT/mTOR signaling pathway, which is frequently overactive in various malignancies [1, 2, 5].