title: Direct small-molecule kinase activation: Novel approaches for a new era of drug discovery.
abstract: The pharmaceutical industry has traditionally targeted the inhibition of dysregulated kinases to treat diseases such as cancer and inflammatory disorders. In contrast to the human genome sequencing project, which aimed to identify novel biological targets, the possibility of activating kinases uses known targets in a novel manner. In an approach that is similar to other target classes (eg, GPCRs and nuclear receptors), transient upregulation of kinase function using small molecules has been increasingly demonstrated to lead to favorable disease outcomes. This review discusses direct small-molecule kinase activators: specifically, how these molecules were discovered, characterized, evaluated and developed into drug leads. The choice of potential targets, the mechanisms of activation and the common strategies used to discover activators are also highlighted.
authors.affiliation: GlaxoSmithKline plc, GSK Medicines Research Centre, Stevenage, Hertfordshire, UK. graham.l.simpson@gsk.com
authors.forename: Graham L
authors.initials: GL
authors.lastname: Simpson
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Hughes
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Washio
authors.forename: Sophie M
authors.initials: SM
authors.lastname: Bertrand
mesh_terms: D064413:3-Phosphoinositide-Dependent Protein Kinases; D000494:Allosteric Regulation; D000818:Animals; D064127:Aurora Kinases; D015195:Drug Design; D055808:Drug Discovery; D004789:Enzyme Activation; D020536:Enzyme Activators / Q000737:chemistry / Q000494:pharmacology*; D005941:Glucokinase / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D015394:Molecular Structure; D010766:Phosphorylation; D011487:Protein Conformation; D011493:Protein Kinase C / Q000378:metabolism; D011494:Protein Kinases / Q000737:chemistry / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011972:Receptor, Insulin / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013329:Structure-Activity Relationship
chemical_list: D020536:Enzyme Activators; D011494:Protein Kinases; D005941:Glucokinase; D011972:Receptor, Insulin; D064413:3-Phosphoinositide-Dependent Protein Kinases; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases; D011493:Protein Kinase C