title: A fragment-based selection approach for the discovery of peptide macrocycles targeting protein kinases.
abstract: Protein kinases are implicated in diverse signaling cascades and have been targeted with small molecules that typically bind the conserved ATP-binding active site. These inhibitors are often promiscuous and target multiple protein kinases, which has led to the development of alternate strategies to discover selective ligands. We have recently described a fragment-based selection approach, where a small-molecule warhead can be non-covalently tethered to a phage-displayed library of cyclic peptides. This approach led to the conversion of the promiscuous kinase inhibitor, staurosporine, into a selective bivalent inhibitor.
authors.affiliation: Department of Chemistry and Biochemistry, University of Arizona, 1306 E. University Blvd., Tucson, AZ, 85721-0041, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Restituyo
authors.forename: Karla
authors.initials: K
authors.lastname: Camacho-Soto
authors.forename: Indraneel
authors.initials: I
authors.lastname: Ghosh
mesh_terms: D000818:Animals; D055808:Drug Discovery; D006801:Humans; D019151:Peptide Library; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000737:chemistry; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry; D011494:Protein Kinases / Q000737:chemistry*; D019311:Staurosporine / Q000737:chemistry
chemical_list: D019151:Peptide Library; D010456:Peptides, Cyclic; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases; D019311:Staurosporine