title: Discovery of a potent and highly selective PDK1 inhibitor via fragment-based drug discovery.
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.
authors: Sunesis Pharmaceuticals, Inc., 395 Oyster Point Blvd., South San Francisco, CA 94080, USA. derlanson@carmot.us
authors: Daniel A
authors: DA
authors: Erlanson
authors: Joseph W
authors: JW
authors: Arndt
authors: Mark T
authors: MT
authors: Cancilla
authors: Kathy
authors: K
authors: Cao
authors: Robert A
authors: RA
authors: Elling
authors: Nicki
authors: N
authors: English
authors: Jessica
authors: J
authors: Friedman
authors: Stig K
authors: SK
authors: Hansen
authors: Cathy
authors: C
authors: Hession
authors: Ingrid
authors: I
authors: Joseph
authors: Gnanasambandam
authors: G
authors: Kumaravel
authors: Wen-Cherng
authors: WC
authors: Lee
authors: Ken E
authors: KE
authors: Lind
authors: Robert S
authors: RS
authors: McDowell
authors: Konrad
authors: K
authors: Miatkowski
authors: Christine
authors: C
authors: Nguyen
authors: Thinh B
authors: TB
authors: Nguyen
authors: Sophia
authors: S
authors: Park
authors: Nuzhat
authors: N
authors: Pathan
authors: David M
authors: DM
authors: Penny
authors: Michael J
authors: MJ
authors: Romanowski
authors: Daniel
authors: D
authors: Scott
authors: Laura
authors: L
authors: Silvian
authors: Robert L
authors: RL
authors: Simmons
authors: Bradley T
authors: BT
authors: Tangonan
authors: Wenjin
authors: W
authors: Yang
authors: Lihong
authors: L
authors: Sun
mesh_terms: D018360:Crystallography, X-Ray; D015195:Drug Design; D055808:Drug Discovery; D004789:Enzyme Activation / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D008954:Models, Biological; D015394:Molecular Structure; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011728:Pyridones / Q000737:chemistry / Q000494:pharmacology; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D011728:Pyridones; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D054852:Small Molecule Libraries; D017346:Protein Serine-Threonine Kinases