title: Extending kinome coverage by analysis of kinase inhibitor broad profiling data.
abstract: The explored kinome was extended with broad profiling using the DiscoveRx and Millipore assay panels. The analysis of the profiling of 3368 selected inhibitors on 456 kinases in the DiscoveRx format delivered several insights. First, the coverage depended on the threshold of the selectivity parameter. Second, the relation between hit confirmation rates and inhibitor selectivity showed unexpectedly that higher selectivity can increase the likelihood of false positives. Third, comparing the coverage of a focused to that of a random library showed that the design based on a maximum number of scaffolds was superior to a limited number of scaffolds. Therefore, selective compounds can be used in target validation, enable the jumpstarting of new kinase drug discovery projects, and chart new biological space via phenotypic screening.
authors.affiliation: Janssen Research & Development, Turnhoutseweg 30, 2340 Beerse, Belgium. Electronic address: ejacoby@its.jnj.com.
authors.forename: Edgar
authors.initials: E
authors.lastname: Jacoby
authors.affiliation: Janssen Research & Development, Turnhoutseweg 30, 2340 Beerse, Belgium.
authors.forename: Gary
authors.initials: G
authors.lastname: Tresadern
authors.affiliation: Janssen Research & Development, La Jolla, 3210 Merryfield Row, San Diego, CA 92121, USA.
authors.forename: Scott
authors.initials: S
authors.lastname: Bembenek
authors.affiliation: Janssen Research & Development, Turnhoutseweg 30, 2340 Beerse, Belgium.
authors.forename: Berthold
authors.initials: B
authors.lastname: Wroblowski
authors.affiliation: Janssen Research & Development, Turnhoutseweg 30, 2340 Beerse, Belgium.
authors.forename: Christophe
authors.initials: C
authors.lastname: Buyck
authors.affiliation: Janssen Research & Development, Turnhoutseweg 30, 2340 Beerse, Belgium.
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Neefs
authors.affiliation: Janssen Research & Development, Spring House, 1400 McKean Road, Spring House, PA 19002, USA.
authors.forename: Dmitrii
authors.initials: D
authors.lastname: Rassokhin
authors.affiliation: Janssen Research & Development, Val de Reuil, Campus de Maigremont, B.P. 615, 27106 Val De Reuil Cedex, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Poncelet
authors.affiliation: KINOMEscan Division of DiscoveRx Corporation, 11180 Roselle Street, Suite D, San Diego, CA 92121, USA.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Hunt
authors.affiliation: Janssen Research & Development, Turnhoutseweg 30, 2340 Beerse, Belgium. Electronic address: hvvlijme@its.jnj.com.
authors.forename: Herman
authors.initials: H
authors.lastname: van Vlijmen
mesh_terms: D030562:Databases, Protein; D055808:Drug Discovery / Q000379:methods*; D057166:High-Throughput Screening Assays; D006801:Humans; D015394:Molecular Structure; D058990:Molecular Targeted Therapy; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D040901:Proteomics / Q000379:methods*; D015398:Signal Transduction / Q000187:drug effects; D054852:Small Molecule Libraries; D013329:Structure-Activity Relationship; D057188:Workflow
chemical_list: D047428:Protein Kinase Inhibitors; D054852:Small Molecule Libraries; D011494:Protein Kinases