title: Selectivity of kinase inhibitor fragments.
abstract: A kinase-focused screening set of fragments has been assembled and has proved successful for the discovery of ligand-efficient hits against many targets. Here we present some of our general conclusions from this exercise. Notably, we present the first profiling results for literature fragments that have previously been used as starting points for optimization against individual kinases. We consider the importance of screening format and the extent to which selectivity is helpful in selecting fragments for progression. Results are also outlined for fragments targeting the DFG-out conformation and for atypical kinases such as PIM1 and lipid kinases.
authors.affiliation: GlaxoSmithKline R&D, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, UK. Paul.A.Bamborough@gsk.com
authors.forename: Paul
authors.initials: P
authors.lastname: Bamborough
authors.forename: Murray J
authors.initials: MJ
authors.lastname: Brown
authors.forename: John A
authors.initials: JA
authors.lastname: Christopher
authors.forename: Chun-wa
authors.initials: CW
authors.lastname: Chung
authors.forename: Geoff W
authors.initials: GW
authors.lastname: Mellor
mesh_terms: D000225:Adenine / Q000737:chemistry; D000255:Adenosine Triphosphate / Q000737:chemistry; D000814:Aniline Compounds / Q000737:chemistry; D001665:Binding Sites; D004791:Enzyme Inhibitors / Q000737:chemistry*; D057166:High-Throughput Screening Assays; D007191:Indazoles / Q000737:chemistry; D007211:Indoles / Q000737:chemistry; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000737:chemistry; D008958:Models, Molecular; D019869:Phosphatidylinositol 3-Kinases / Q000737:chemistry; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010770:Phosphotransferases / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry; D051573:Proto-Oncogene Proteins c-pim-1 / Q000037:antagonists & inhibitors / Q000737:chemistry; D011725:Pyridines / Q000737:chemistry; D011743:Pyrimidines / Q000737:chemistry; D021281:Quantitative Structure-Activity Relationship; D054852:Small Molecule Libraries
chemical_list: D000225:Adenine; D000255:Adenosine Triphosphate; D000814:Aniline Compounds; D004791:Enzyme Inhibitors; D007191:Indazoles; D007211:Indoles; D007527:Isoenzymes; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010770:Phosphotransferases; D047428:Protein Kinase Inhibitors; D051573:Proto-Oncogene Proteins c-pim-1; D011725:Pyridines; D011743:Pyrimidines; D054852:Small Molecule Libraries