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Discovery of a potent and highly selective PDK1 inhibitor via fragment-based drug discovery |
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| Authors: | Erlanson Daniel A Arndt Joseph W Cancilla Mark T Cao Kathy Elling Robert A English Nicki Friedman Jessica Hansen Stig K Hession Cathy Joseph Ingrid Kumaravel Gnanasambandam Lee Wen-Cherng Lind Ken E McDowell Robert S Miatkowski Konrad Nguyen Christine Nguyen Thinh B Park Sophia Pathan Nuzhat Penny David M Romanowski Michael J Scott Daniel Silvian Laura Simmons Robert L Tangonan Bradley T Yang Wenjin Sun Lihong |
| Affiliation: | a Sunesis Pharmaceuticals, Inc., 395 Oyster Point Blvd., South San Francisco, CA 94080, USA b Biogen Idec, Inc., 14 Cambridge Center, Cambridge, MA 02142, USA |
| Abstract: | 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. |
| Keywords: | PDK1 Selective Tethering Pyridinone DFG-out Fragment-based drug discovery |
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