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.