Phosphoinositide 3-kinase alpha and delta (PI3K-α and PI3K-δ) (PI3K-α/δ)

Class I Phosphoinositide 3-kinases (PI3K) are essential lipid kinases that regulate a wide array of cellular processes by generating the second messenger phosphatidylinositol 3,4,5-trisphosphate (PIP3) at the plasma membrane (UniProt P42336, O00329). The alpha (α) isoform, encoded by the PIK3CA gene, is ubiquitously expressed and serves as a primary mediator of growth factor and insulin signaling; it is one of the most frequently mutated oncogenes in human solid tumors, particularly breast and colorectal cancers (Nature Reviews Cancer, 2021). The delta (δ) isoform, encoded by PIK3CD, is primarily restricted to hematopoietic cells where it governs B-cell signaling, T-cell activation, and overall immune homeostasis (Cell, 2017). Therapeutic targeting of these isoforms involves small-molecule inhibitors that bind to the ATP-binding pocket of the p110 catalytic subunits, effectively dampening the hyperactive AKT/mTOR pathway found in many malignancies (FDA: Piqray, Aliqopa). While α-selective inhibitors like alpelisib are used to treat PIK3CA-mutated breast cancer, δ-selective or dual α/δ inhibitors like copanlisib are employed in hematologic cancers such as follicular lymphoma (StatPearls, 2023). However, clinical use is often limited by isoform-specific toxicities, including hyperglycemia and rash for PI3K-α inhibition, and immune-mediated colitis, hepatotoxicity, and infections for PI3K-δ inhibition (Nature Reviews Cancer, 2021).

Other names

PIK3CA and PIK3CDp110α and p110δPhosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha and deltaClass I PI3K alpha and delta

Competitive inhibition of the ATP-binding site of the p110 catalytic subunits of PI3K-α and PI3K-δ, preventing the phosphorylation of PIP2 to PIP3 and subsequent activation of downstream AKT/mTOR signaling (Nature Reviews Cancer, 2021; FDA Label: Aliqopa).