Class II phosphoinositide 3-kinases (Class II PI3Ks)

Class II phosphoinositide 3-kinases (Class II PI3Ks) are a distinct subgroup of the PI3K family, comprising three isoforms: PI3K-C2α, PI3K-C2β, and PI3K-C2γ. Unlike the well-studied Class I PI3Ks, Class II enzymes are large monomeric proteins that primarily catalyze the synthesis of phosphatidylinositol 3-phosphate (PI3P) and phosphatidylinositol 3,4-bisphosphate (PI(3,4)P2) [PMID: 28263302]. They play critical roles in regulating membrane trafficking, endocytosis, and primary cilia function, which are essential for cellular homeostasis and signal transduction [PMID: 30635421]. Dysregulation of Class II PI3Ks is implicated in various pathologies, including cancer progression, metabolic disorders like type 2 diabetes, and cardiovascular diseases such as thrombosis [PMID: 29439111]. While most clinical PI3K inhibitors target Class I isoforms, Class II PI3Ks are emerging as promising therapeutic targets for specific indications, such as antithrombotic therapy and metabolic regulation [PMID: 31112131]. Developing isoform-specific inhibitors remains a significant challenge due to the structural similarities within the kinase domain, but recent advances in small-molecule discovery are beginning to yield selective tools for these enzymes [PMID: 32433948].

Other names

PI3K Class IIPhosphatidylinositol 3-kinase Class IIPI3K-C2PIK3C2Phosphoinositide 3-kinase Class 2

Inhibition of the catalytic activity of Class II PI3K isoforms (C2α, C2β, C2γ) to prevent the phosphorylation of phosphatidylinositol (PI) and phosphatidylinositol 4-phosphate (PI4P) into the signaling lipids PI3P and PI(3,4)P2, thereby modulating membrane trafficking and intracellular signaling pathways.