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Discovery of a potent and highly selective PDK1 inhibitor via fragment-based drug discovery

2011; Elsevier BV; Volume: 21; Issue: 10 Linguagem: Inglês

10.1016/j.bmcl.2011.03.032

1464-3405

Daniel A. Erlanson, Joseph W. Arndt, Mark T. Cancilla, Kathy Cao, R.A. Elling, Nicki English, Jessica Friedman, Stig K. Hansen, Cathy Hession, Ingrid B.J. Joseph, G. Kumaravel, Wen‐Cherng Lee, Ken Lind, Robert S. McDowell, Konrad Miatkowski, Christine Nguyen, Thinh B. Nguyen, Sophia Park, Nazima Pathan, David M. Penny, M.J. Romanowski, Daniel A. Scott, Laura Silvian, Robert L. Simmons, Bradley T. Tangonan, Wenjin Yang, Sun Li-hong,

Biochemical and Molecular Research

We report the use of a fragment-based lead discovery method, Tethering with extenders, to discover a pyridinone fragment that binds in an adaptive site of the protein PDK1. With subsequent medicinal chemistry, this led to the discovery of a potent and highly selective inhibitor of PDK1, which binds in the 'DFG-out' conformation.