Structure-based drug design enables conversion of a DFG-in binding CSF-1R kinase inhibitor to a DFG-out binding mode
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Acknowledgments
The authors thank Daniel Walker and Michael Ennis for critical review of this manuscript, and the Advanced Photon Source and the staff at beamline 21ID-D for their help in the collection of diffraction data.
References and notes (11)
- et al.
Trends Cell Biol.
(2004) - et al.
Bioorg. Med. Chem. Lett.
(2007)et al.Bioorg. Med. Chem. Lett.
(2008)et al.Bioorg. Med. Chem. Lett.
(2008)et al.J. Med. Chem.
(2009)et al.J. Neuroimmunol.
(2008)et al.Eur. J. Immunol.
(2008)et al.Proc. Natl. Acad. Sci. U.S.A.
(2005)et al.J. Pharmacol. Exp. Ther.
(2008)et al.Ann. Rep. Med. Chem.
(2009)et al.Mol. Cancer Ther.
(2009) - et al.
Nat. Struct. Biol.
(2002)et al.Chem. Biol.
(2005)Nat. Rev. Drug Disc.
(2004)Curr. Top. Med. Chem.
(2006)
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