title: A novel mechanism by which small molecule inhibitors induce the DFG flip in Aurora A.
abstract: Most protein kinases share a DFG (Asp-Phe-Gly) motif in the ATP site that can assume two distinct conformations, the active DFG-in and the inactive DFG-out states. Small molecule inhibitors able to induce the DFG-out state have received considerable attention in kinase drug discovery. Using a typical DFG-in inhibitor scaffold of Aurora A, a kinase involved in the regulation of cell division, we found that halogen and nitrile substituents directed at the N-terminally flanking residue Ala273 induced global conformational changes in the enzyme, leading to DFG-out inhibitors that are among the most potent Aurora A inhibitors reported to date. The data suggest an unprecedented mechanism of action, in which induced-dipole forces along the Ala273 side chain alter the charge distribution of the DFG backbone, allowing the DFG to unwind. As the ADFG sequence and three-dimensional structure is highly conserved, DFG-out inhibitors of other kinases may be designed by specifically targeting the flanking alanine residue with electric dipoles.
authors.affiliation: Drug Discovery Department, Moffitt Cancer Center and Research Institute, Tampa, Florida 33612, United States.
authors.forename: Mathew P
authors.initials: MP
authors.lastname: Martin
authors.forename: Jin-Yi
authors.initials: JY
authors.lastname: Zhu
authors.forename: Harshani R
authors.initials: HR
authors.lastname: Lawrence
authors.forename: Roberta
authors.initials: R
authors.lastname: Pireddu
authors.forename: Yunting
authors.initials: Y
authors.lastname: Luo
authors.forename: Riazul
authors.initials: R
authors.lastname: Alam
authors.forename: Sevil
authors.initials: S
authors.lastname: Ozcan
authors.forename: Said M
authors.initials: SM
authors.lastname: Sebti
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Lawrence
authors.forename: Ernst
authors.initials: E
authors.lastname: Schönbrunn
mesh_terms: D064127:Aurora Kinases; D002455:Cell Division; D015195:Drug Design; D006801:Humans; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology*; D011487:Protein Conformation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry* / Q000187:drug effects*
chemical_list: C553185:DFG peptide; D009842:Oligopeptides; D047428:Protein Kinase Inhibitors; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases