Phosphoinositide 3-kinase alpha and delta isoforms (PI3Kα/PI3Kδ)

Phosphoinositide 3-kinase alpha (PI3Kα) and delta (PI3Kδ) are lipid kinases belonging to the Class I PI3K family, which play critical roles in regulating cell growth, survival, and metabolism (UniProt P42336, O00329). PI3Kα is ubiquitously expressed and is a key mediator of insulin signaling and growth factor-driven proliferation, often found mutated or overexpressed in various solid tumors (PubMed: 29735922). In contrast, PI3Kδ expression is largely restricted to hematopoietic cells, where it is essential for B-cell development, activation, and signaling through the B-cell receptor (PubMed: 24651010). Dual inhibition of these isoforms, as seen with the drug copanlisib, provides a potent therapeutic strategy by simultaneously targeting the oncogenic signaling in tumor cells and the supportive microenvironment in hematologic malignancies (FDA Label: Aliqopa). This combined approach is particularly effective in treating relapsed or refractory follicular lymphoma, where both isoforms contribute to disease progression (PubChem CID: 44605602).

Other names

PIK3CA/PIK3CDPhosphatidylinositol 3-kinase catalytic subunit alpha and deltap110α/p110δPI3-kinase subunit alpha/delta

Copanlisib acts as a potent, reversible inhibitor of Class I PI3K with predominant inhibitory activity against the PI3Kα and PI3Kδ isoforms (FDA Label: Aliqopa). By binding to the ATP-binding site of the p110α and p110δ catalytic subunits, it prevents the phosphorylation of phosphatidylinositol 4,5-bisphosphate (PIP2) into phosphatidylinositol 3,4,5-trisphosphate (PIP3) (PubMed: 28947440). This blockade inhibits the downstream activation of the AKT/mTOR signaling pathway, leading to decreased cell proliferation and induction of apoptosis in malignant cells (PubChem CID: 44605602).