Development of Selective Phosphatidylinositol 5-Phosphate 4-Kinase γ Inhibitors with a Non-ATP-competitive, Allosteric Binding Mode
Helen K. Boffey, Timothy P. C. Rooney, Henriëtte M. G. Willems, Simon Edwards, Christopher Green, Tina Howard, D. Ogg, Tamara Romero, Duncan E. Scott, David Winpenny, James A. Duce, John Skidmore, Jonathan H. Clarke, Stephen P. Andrews
Abstract
). These improvements enabled the demonstration that this chemotype engages PI5P4Kγ in intact cells and that compounds from this series do not inhibit PI5P4Kα or PI5P4Kβ. Furthermore, the first X-ray structure of PI5P4Kγ bound to an inhibitor has been determined with this chemotype, confirming an allosteric binding mode. An exemplar from this chemical series adopted two distinct modes of inhibition, including through binding to a putative lipid interaction site which is 18 Å from the ATP pocket.
Topics & Concepts
Allosteric regulationChemistryKinasePhosphatidylinositolBiochemistryMode of actionBinding siteEnzymeCell biologyBiologyCalcium signaling and nucleotide metabolismCellular transport and secretionPhagocytosis and Immune Regulation