title: Fragment based discovery of a novel and selective PI3 kinase inhibitor.
abstract: We report the use of fragment screening and fragment based drug design to develop a PI3γ kinase fragment hit into a lead. Initial fragment hits were discovered by high concentration biochemical screening, followed by a round of virtual screening to identify additional ligand efficient fragments. These were developed into potent and ligand efficient lead compounds using structure guided fragment growing and merging strategies. This led to a potent, selective, and cell permeable PI3γ kinase inhibitor with good metabolic stability that was useful as a preclinical tool compound.
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer Global Research and Development, Sandwich Laboratories, Ramsgate Road, Sandwich, Kent CT13 9NJ, UK. samantha.hughes@pfizer.com
authors.forename: Samantha J
authors.initials: SJ
authors.lastname: Hughes
authors.forename: David S
authors.initials: DS
authors.lastname: Millan
authors.forename: Iain C
authors.initials: IC
authors.lastname: Kilty
authors.forename: Russell A
authors.initials: RA
authors.lastname: Lewthwaite
authors.forename: John P
authors.initials: JP
authors.lastname: Mathias
authors.forename: Mark A
authors.initials: MA
authors.lastname: O'Reilly
authors.forename: Andrew
authors.initials: A
authors.lastname: Pannifer
authors.forename: Anne
authors.initials: A
authors.lastname: Phelan
authors.forename: Frank
authors.initials: F
authors.lastname: Stühmeier
authors.forename: Darren A
authors.initials: DA
authors.lastname: Baldock
authors.forename: David G
authors.initials: DG
authors.lastname: Brown
mesh_terms: D002463:Cell Membrane Permeability / Q000187:drug effects; D055808:Drug Discovery; D004355:Drug Stability; D008958:Models, Molecular; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors