Properties of FDA-approved small molecule phosphatidylinositol 3-kinase inhibitors prescribed for the treatment of malignancies

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 p110 alpha, p110 beta, p110 delta, and p110 gamma catalytic subunits. These catalytic subunits are constitutively bound to regulatory subunits (p85 alpha, p85 beta, p55 gamma, p101, and p87 proteins). The p85/p55 regulatory subunits heterodimerize with p110 alpha or p110 delta thereby forming complexes that are regulated chiefly by receptor protein-tyrosine kinases. The p101 and p87 subunits heterodimerize with p110 gamma to form complexes that are regulated mainly by G protein-coupled receptors (GPCRs). Complexes containing the p110 beta 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 alpha-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 A; this distance in active PI 3-kinases is about 18 A. 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-alpha inhibitor used for the treatment of breast cancer. Copanlisib, duvelisib, idelalisib, and umbralisib are PI 3-kinase-delta 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-a. Of the five approved drugs, all are orally bioavailable except copanlisib. Idelalisib interacts with the active conformation of PI 3-kinase-delta and is classified as a type I inhibitor. Alpelisib and copanlisib interact with inactive PI 3-kinase-alpha and PI 3-kinase-gamma, respectively, and are classified as a type I 1/2 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-alpha, 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.

Automated summary

The discovery of the phosphatidylinositol 3-kinase (PI 3-kinase) pathway has provided a major advance in understanding eukaryotic signal transduction, leading to the development of drugs targeting oncogenic mutants. PI 3-kinases are divided into three classes, with Class I PI 3-kinases being the main subject, catalyzing the phosphorylation of phosphatidylinositol-4,5-bisphosphate (PI-4,5-P2) to generate phosphatidylinositol-3,4,5-trisphosphate (PIP3). These kinases interact with various receptor and regulatory subunits to affect cell growth and survival.