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ACS Chem Biol. 2012 Apr 20;7(4):698-706. doi: 10.1021/cb200508b. Epub 2012 Jan 27.

A novel mechanism by which small molecule inhibitors induce the DFG flip in Aurora A.

Author information

1
Drug Discovery Department, Moffitt Cancer Center and Research Institute, Tampa, Florida 33612, United States.

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.

PMID:
22248356
PMCID:
PMC4429595
DOI:
10.1021/cb200508b
[Indexed for MEDLINE]
Free PMC Article

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