Martin, Mathew P. Zhu, Jin-Yi Lawrence, Harshani R. Pireddu, Roberta Luo, Yunting Alam, Riazul Ozcan, Sevil Sebti, Said M. Lawrence, Nicholas J. SchoĢˆnbrunn, Ernst A Novel Mechanism by Which Small Molecule Inhibitors Induce the DFG Flip in Aurora A 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. kinase drug discovery;residue Ala 273;Small molecule inhibitors;Novel Mechanism;cell division;charge distribution;DFG Flip;Ala 273 side chain;alanine residue;Aurora AMost protein kinases share;DFG backbone;Small Molecule Inhibitors Induce;ADFG sequence;nitrile substituents;ATP site 2012-04-20
    https://acs.figshare.com/articles/journal_contribution/A_Novel_Mechanism_by_Which_Small_Molecule_Inhibitors_Induce_the_DFG_Flip_in_Aurora_A/2529118
10.1021/cb200508b.s001