title: Highly specific, bisubstrate-competitive Src inhibitors from DNA-templated macrocycles.
abstract: Protein kinases are attractive therapeutic targets, but their high sequence and structural conservation complicates the development of specific inhibitors. We recently identified, in a DNA-templated macrocycle library, inhibitors with unusually high selectivity among Src-family kinases. Starting from these compounds, we developed and characterized in molecular detail potent macrocyclic inhibitors of Src kinase and its cancer-associated 'gatekeeper' mutant. We solved two cocrystal structures of macrocycles bound to Src kinase. These structures reveal the molecular basis of the combined ATP- and substrate peptide-competitive inhibitory mechanism and the remarkable kinase specificity of the compounds. The most potent compounds inhibit Src activity in cultured mammalian cells. Our work establishes that macrocycles can inhibit protein kinases through a bisubstrate-competitive mechanism with high potency and exceptional specificity, reveals the precise molecular basis for their desirable properties and provides new insights into the development of Src-specific inhibitors with potential therapeutic relevance.
authors.affiliation: Department of Pharmacological Sciences, Stony Brook University, Stony Brook, New York, USA.
authors.forename: George
authors.initials: G
authors.lastname: Georghiou
authors.forename: Ralph E
authors.initials: RE
authors.lastname: Kleiner
authors.forename: Michael
authors.initials: M
authors.lastname: Pulkoski-Gross
authors.forename: David R
authors.initials: DR
authors.lastname: Liu
authors.forename: Markus A
authors.initials: MA
authors.lastname: Seeliger
mesh_terms: D016475:3T3 Cells; D000818:Animals; D001667:Binding, Competitive; D018360:Crystallography, X-Ray; D004247:DNA / Q000737:chemistry; D006801:Humans; D047028:Macrocyclic Compounds / Q000737:chemistry*; D051379:Mice; D015394:Molecular Structure; D009154:Mutation; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D017434:Protein Structure, Tertiary; D051572:Proto-Oncogene Proteins c-hck / Q000378:metabolism; D019061:src-Family Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: D047028:Macrocyclic Compounds; D047428:Protein Kinase Inhibitors; D004247:DNA; C496631:HCK protein, human; D051572:Proto-Oncogene Proteins c-hck; D019061:src-Family Kinases