title: For a PDK1 inhibitor, the substrate matters.
abstract: More than 20 protein kinases are directly activated by 3-phosphoinositide-dependent kinase 1 (PDK1), which is a central component of the pathways that regulate cell growth, proliferation and survival. Despite the importance of PDK1 in cell signalling, highly selective PDK1 inhibitors have not been described. In this issue of the Biochemical Journal, Dario Alessi's group and their collaborators at GlaxoSmithKline report GSK2334470, a potent and selective PDK1 inhibitor. They show that this compound blocks the phosphorylation of known PDK1 substrates, but surprisingly find that the potency and kinetics of inhibition vary for different PDK1 targets. This substrate-specific inhibition has implications for the development of PDK1 inhibitors as drugs.
authors.affiliation: The Rockefeller University, New York, NY 10065, USA. zknight@rockefeller.edu
authors.forename: Zachary A
authors.initials: ZA
authors.lastname: Knight
mesh_terms: D006801:Humans; D007191:Indazoles / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000494:pharmacology*; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D015398:Signal Transduction / Q000187:drug effects; D013379:Substrate Specificity
chemical_list: C555257:GSK 2334470; D007191:Indazoles; C000631429:PDK1 protein, human; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D017346:Protein Serine-Threonine Kinases