Phosphatidylinositol 3-kinase alpha (PI3Kα) and Phosphatidylinositol 3-kinase delta (PI3Kδ) (PI3Kα (for alpha) / PI3Kδ (for delta))

Phosphatidylinositol 3-kinase alpha (PI3Kα) and phosphatidylinositol 3-kinase delta (PI3Kδ) are class I lipid kinases that catalyze the phosphorylation of phosphatidylinositol 4,5-bisphosphate (PIP2) to produce phosphatidylinositol 3,4,5-trisphosphate (PIP3), a critical second messenger in cell signaling. PI3Kα is ubiquitously expressed and is frequently mutated in solid tumors, driving oncogenic signaling and tumorigenesis, whereas PI3Kδ is predominantly expressed in leukocytes and plays a pivotal role in immune cell development and function. Both kinases are targets of small molecule inhibitors in oncology and immune-mediated diseases, with approved inhibitors such as alpelisib (PI3Kα) and idelalisib (PI3Kδ). Dual inhibition (PI3Kα/δ) may be therapeutically advantageous in certain tumors and lymphoid malignancies. Because of their central role in cell growth and survival, as well as immune regulation, PI3Kα and PI3Kδ are considered key targets in targeted therapy, but inhibition is associated with significant safety concerns, particularly due to on-target toxicities affecting glucose homeostasis and immune function.

Other names

PI3K alpha (for PI3Kα)PI3K delta (for PI3Kδ)p110α (for PI3Kα)p110δ (for PI3Kδ)PIK3CA (gene for PI3Kα)PIK3CD (gene for PI3Kδ)Phosphoinositide 3-kinase alphaPhosphoinositide 3-kinase delta

Inhibition of PI3K kinase activity, thereby blocking formation of the second messenger PIP3 and downstream AKT/mTOR signaling critical for cell survival, proliferation, and metabolism. Suppression of PI3Kδ particularly affects B-cell receptor-mediated signaling and is used in hematological cancers. Inhibition of PI3Kα suppresses tumor cell growth in solid tumors driven by PIK3CA mutations.