title: A guide to picking the most selective kinase inhibitor tool compounds for pharmacological validation of drug targets.
abstract: To establish the druggability of a target, genetic validation needs to be supplemented with pharmacological validation. Pharmacological studies, especially in the kinase field, are hampered by the fact that many reference inhibitors are not fully selective for one target. Fortunately, the initial trickle of selective inhibitors released in the public domain has steadily swelled into a stream. However, rationally picking the most selective tool compound out of the increasing amounts of available inhibitors has become progressively difficult due to the lack of accurate quantitative descriptors of drug selectivity. A recently published approach, termed 'selectivity entropy', is an improved way of expressing selectivity as a single-value parameter and enables rank ordering of inhibitors. We provide a guide to select the best tool compounds for pharmacological validation experiments of candidate drug targets using selectivity entropy. In addition, we recommend which inhibitors to use for studying the biology of the 20 most investigated kinases that are clinically relevant: Abl (ABL1), AKT1, ALK, Aurora A/B, CDKs, MET, CSF1R (FMS), EGFR, FLT3, ERBB2 (HER2), IKBKB (IKK2), JAK2/3, JNK1/2/3 (MAPK8/9/10), MEK1/2, PLK1, PI3Ks, p38α (MAPK14), BRAF, SRC and VEGFR2 (KDR).
authors.affiliation: Netherlands Translational Research Center BV, Oss, the Netherlands. joost.uitdehaag@ntrc.nl
authors.forename: Joost C M
authors.initials: JC
authors.lastname: Uitdehaag
authors.forename: Folkert
authors.initials: F
authors.lastname: Verkaar
authors.forename: Husam
authors.initials: H
authors.lastname: Alwan
authors.forename: Jos
authors.initials: J
authors.lastname: de Man
authors.forename: Rogier C
authors.initials: RC
authors.lastname: Buijsman
authors.forename: Guido J R
authors.initials: GJ
authors.lastname: Zaman
mesh_terms: D000818:Animals; D055808:Drug Discovery / Q000379:methods*; D019277:Entropy; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D010770:Phosphotransferases / Q000037:antagonists & inhibitors*; D011485:Protein Binding; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D004791:Enzyme Inhibitors; D010770:Phosphotransferases