Class I phosphoinositide 3-kinase (PI3K) (PI3K)

Class I phosphoinositide 3-kinases (PI3Ks) are a family of heterodimeric lipid kinases consisting of a catalytic p110 subunit (isoforms α, β, δ, and γ) and a regulatory subunit [4, 9]. They play a central role in the PI3K/AKT/mTOR signaling pathway, which regulates fundamental cellular processes such as growth, proliferation, survival, and metabolism [1, 11]. In many cancers, this pathway is constitutively activated through mutations in the PIK3CA gene or loss of the tumor suppressor PTEN, leading to uncontrolled tumor growth and resistance to therapy [8, 13]. Buparlisib (BKM120) is an orally bioavailable pan-Class I PI3K inhibitor that competitively binds to the ATP-binding pocket of all four isoforms [2, 17]. By blocking the production of the second messenger phosphatidylinositol-3,4,5-trisphosphate (PIP3), buparlisib inhibits downstream signaling, inducing apoptosis and growth arrest in cancer cells [3, 5]. While effective in preclinical models, its clinical use has been limited by significant toxicities, including hyperglycemia and psychiatric side effects like depression and anxiety, the latter attributed to its ability to cross the blood-brain barrier [10, 15]. Additionally, buparlisib has been noted to have off-target effects on microtubule polymerization at higher concentrations [6].

Other names

Class I phosphatidylinositol 3-kinasepan-Class I PI3Kp110 isoformsPhosphoinositide 3-kinase Class I

ATP-competitive inhibition of Class I PI3K isoforms (p110α, p110β, p110δ, and p110γ), preventing the phosphorylation of phosphatidylinositol 4,5-bisphosphate (PIP2) to phosphatidylinositol 3,4,5-trisphosphate (PIP3), thereby blocking the PI3K/AKT/mTOR signaling pathway.