RESUMEN
Obesity is a disorder with an increasing prevalence, which impairs the life quality of patients and intensifies societal health care costs. The development of safe and innovative prevention strategies and therapeutic approaches is thus of great importance. The complex pathophysiology of obesity involves multiple signaling pathways that influence energy metabolism in different tissues. The phosphatidylinositol 3-kinases (PI3K)/protein kinase B (AKT) pathway is critical for the metabolic homeostasis and its function in insulin-sensitive tissues is described in the context of health, obesity and obesity-related complications. The PI3K family participates in the regulation of diverse physiological processes including but not limited to cell growth, survival, differentiation, autophagy, chemotaxis, and metabolism depending on the cellular context. AKT is downstream of PI3K in the insulin signaling pathway, and promotes multiple cellular processes by targeting a plethora of regulatory proteins that control glucose and lipid metabolism. Natural products are essential for prevention and treatment of many human diseases, including obesity. Anti-obesity natural compounds effect multiple pathophysiological mechanisms involved in obesity development. Numerous recent preclinical studies reveal the advances in using plant secondary metabolites to target the PI3K/AKT signaling pathway for obesity management. In this paper the druggability of PI3K as a target for compounds with anti-obesity potential is evaluated. Perspectives on the strategies and limitations for clinical implementation of obesity management using natural compounds modulating the PI3K/AKT pathway are suggested.
Asunto(s)
Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , Humanos , Insulina , Fosfatidilinositol 3-Quinasa/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal , Obesidad/metabolismoRESUMEN
The discovery of the phosphatidylinositol 3-kinase (PI 3-kinase) pathway was a major advance in understanding eukaryotic signal transduction. The high frequency of PI 3-kinase pathway mutations in many cancers stimulated the development of drugs targeting these oncogenic mutants. The PI 3-kinases are divided into three classes and Class I PI 3-kinases, which catalyze the phosphorylation of phosphatidylinositol-4,5-bisphosphate (PI-4,5-P2) to generate phosphatidylinositol-3,4,5-trisphosphate (PIP3), are the main subject of this review. The class I PI 3-kinases are made up of p110α, p110ß, p110δ, and p110γ catalytic subunits. These catalytic subunits are constitutively bound to regulatory subunits (p85α, p85ß, p55γ, p101, and p87 proteins). The p85/p55 regulatory subunits heterodimerize with p110α or p110δ thereby forming complexes that are regulated chiefly by receptor protein-tyrosine kinases. The p101 and p87 subunits heterodimerize with p110γ to form complexes that are regulated mainly by G protein-coupled receptors (GPCRs). Complexes containing the p110ß subunit are activated by receptor protein-tyrosine kinases as well as GPCRs. Following the generation of PIP3, the AKT and mTOR protein-serine/threonine kinases are activated leading to cell growth, proliferation, and survival. Like protein kinases, the PI 3-kinase domains consist of a bilobed structure connected by a hinge-linker segment. ATP and most PI 3-kinase and protein kinase inhibitors form hydrogen bonds with hinge residues. The small and large lobes of PI 3-kinases and protein kinases have a very similar three-dimensional structure called the protein kinase fold. Both PI 3-kinases and eukaryotic protein kinases possess an activation segment that begins with a DFG triad (Asp-Phe-Gly); the activation segment of protein kinases usually ends with an APE (Ala-Pro-Glu) signature while that of PI 3-kinases ends with a PFxLT (Pro-Phe-Xxx-Leu-Thr) signature. Dormant PI 3-kinases have a collapsed activation loop and active PI 3-kinases have an extended activation loop. The distance between the α-carbon atom of the DFG-D residue at the beginning of the activation loop and that of the PFxLT-F residue at the end of the activation loop in dormant PI 3-kinases is about 13 Å; this distance in active PI 3-kinases is about 18 Å. The protein kinase catalytic loop has an HRD (His-Arg-Asp) signature while that of the PI 3-kinases reverses the order with a DRH triad. Alpelisib is an orally effective FDA-approved PI 3-kinase-α inhibitor used for the treatment of breast cancer. Copanlisib, duvelisib, idelalisib, and umbralisib are PI 3-kinase-δ inhibitors that are approved for the third-line treatment of follicular lymphomas and other hematological disorders. Copanlisib is also a potent inhibitor of PI 3-kinase-α. Of the five approved drugs, all are orally bioavailable except copanlisib. Idelalisib interacts with the active conformation of PI 3-kinase-δ and is classified as a type I inhibitor. Alpelisib and copanlisib interact with inactive PI 3-kinase-α and PI 3-kinase-γ, respectively, and are classified as a type I½ antagonists. Except for umbralisib with a molecular weight of 571.5, all five drugs conform to the Lipinski rule of five for oral effectiveness. Copanlisib, however, must be given intravenously. Alpelisib and copanlisib inhibit PI 3-kinase-α, which is involved in insulin signaling, and both drugs promote insulin-resistance and produce hyperglycemia. The five FDA-approved PI 3-kinase inhibitors produce significant on-target toxicities, more so than many approved protein kinase antagonists. The development of PI 3-kinase inhibitors with fewer toxicities is an important long-term therapeutic goal.