Phosphoinositide 3-kinase (PI3K) (PI3K)

Phosphoinositide 3-kinases (PI3Ks) are a family of intracellular lipid kinases that orchestrate a wide array of cellular functions, including growth, proliferation, differentiation, motility, and survival [1]. These enzymes are categorized into three classes (I, II, and III) based on their structure and substrate specificity, with Class I being the most extensively studied in human disease [2]. PI3Ks function by phosphorylating the 3-hydroxyl group of the inositol ring in phosphoinositides, generating second messengers like phosphatidylinositol 3,4,5-trisphosphate (PIP3) [3]. This process triggers the recruitment and activation of downstream effectors, most notably the AKT/mTOR signaling axis [4]. Hyperactivation of the PI3K pathway is a hallmark of many human cancers, often driven by gain-of-function mutations in the PIK3CA gene or loss of the PTEN phosphatase [5]. Therapeutic strategies targeting the PI3K family include pan-PI3K inhibitors and isoform-specific inhibitors, several of which are approved for treating breast cancer and hematologic malignancies [6]. Despite their clinical utility, PI3K inhibitors are associated with significant side effects, such as hyperglycemia and immune-mediated toxicities, which necessitate careful patient monitoring [7]. References: [1] Cantley LC (2002) Science 296:1655. [2] Vanhaesebroeck B, et al. (2010) Nat Rev Mol Cell Biol 11:329. [3] Fruman DA, et al. (2017) Cell 170:605. [4] Manning BD, Toker A (2017) Cell 169:381. [5] Samuels Y, et al. (2004) Science 304:554. [6] Janku F, et al. (2018) Nat Rev Clin Oncol 15:273. [7] Esposito A, et al. (2019) Biol Targets Ther 13:131.

Other names

Phosphatidylinositol 3-kinasePI 3-kinasePI3-kinasePhosphatidylinositol-4,5-bisphosphate 3-kinasePtdIns 3-kinase

Inhibition of the ATP-binding site of PI3K catalytic subunits, preventing the conversion of phosphatidylinositol 4,5-bisphosphate (PIP2) to phosphatidylinositol 3,4,5-trisphosphate (PIP3) and subsequent activation of the AKT/mTOR signaling pathway [3, 6].