Chemical approaches to study protein and lipid phosphorylation

Protein and lipid kinases direct signal transduction by the phosphorylation of their substrates. Elucidating kinase-mediated signaling pathways and validating specific kinases as targets for drug development are central goals of biomedical research. Chapter 1 describes the biochemical criteria that define the potency and selectivity of kinase inhibitors in cells. Chapter 2 describes a chemical strategy for targeting proteolysis to sites of protein phosphorylation. Chapter 3 describes isoform-specific inhibitors of PI3-kinase based on an arylmorpholine scaffold. Chapter 4 describes the role of the gatekeeper residue in PI3-kinases in controlling inhibitor sensitivity. Chapter 5 describes a pharmacological map of the PI3-K family and the role of PI3-K isoforms in insulin signaling.