A Novel Mechanism by Which Small Molecule Inhibitors Induce the DFG Flip in Aurora A

作者：Martin Mathew P; Zhu Jin Yi; Lawrence Harshani R; Pireddu Roberta; Luo Yunting; Alam Riazul; Ozcan Sevil; Sebti Said M; Lawrence Nicholas J; Schoenbrunn Ernst

来源：ACS Chemical Biology, 2012, 7(4): 698-706.

DOI：10.1021/cb200508b

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.

• 出版日期2012-4