title: Aminoindazole PDK1 Inhibitors: A Case Study in Fragment-Based Drug Discovery.
abstract: Fragment screening of phosphoinositide-dependent kinase-1 (PDK1) in a biochemical kinase assay afforded hits that were characterized and prioritized based on ligand efficiency and binding interactions with PDK1 as determined by NMR. Subsequent crystallography and follow-up screening led to the discovery of aminoindazole 19, a potent leadlike PDK1 inhibitor with high ligand efficiency. Well-defined structure-activity relationships and protein crystallography provide a basis for further elaboration and optimization of 19 as a PDK1 inhibitor.
authors.affiliation: Oncology Research, Signal Transduction DPU Medicinal Chemistry.
authors.forename: Jesús R
authors.initials: JR
authors.lastname: Medina
authors.affiliation: Oncology Research, Signal Transduction DPU Medicinal Chemistry.
authors.forename: Charles W
authors.initials: CW
authors.lastname: Blackledge
authors.affiliation: Oncology Research, Signal Transduction DPU Medicinal Chemistry.
authors.forename: Dirk A
authors.initials: DA
authors.lastname: Heerding
authors.affiliation: Molecular Discovery Research, Computational and Structural Chemistry.
authors.forename: Nino
authors.initials: N
authors.lastname: Campobasso
authors.affiliation: Molecular Discovery Research, Computational and Structural Chemistry.
authors.forename: Paris
authors.initials: P
authors.lastname: Ward
authors.affiliation: Molecular Discovery Research, Analytical Chemistry.
authors.forename: Jacques
authors.initials: J
authors.lastname: Briand
authors.affiliation: Molecular Discovery Research, Screening and Compound Profiling, GlaxoSmithKline, Research Triangle Park, North Carolina 27709.
authors.forename: Lois
authors.initials: L
authors.lastname: Wright
authors.affiliation: Oncology Research, Signal Transduction DPU Medicinal Chemistry.
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Axten
keywords: Aminoindazole PDK1 inhibitors; binding interactions; fragment-based drug discovery; ligand efficiency