title: Directed modulation of protein kinase C isozyme selectivity with bisubstrate-based inhibitors.
abstract: Kinases present an attractive target for drug development, since they are involved in vital cellular processes and are implicated in a variety of diseases, such as cancer and diabetes. However, obtaining selectivity for a specific kinase over others is difficult since many current kinase inhibitors exclusively target the highly conserved kinase ATP binding domain. Previously, a microarray-based strategy to discover so-called bisubstrate-based inhibitors that target the more specific peptide binding groove in addition to the ATP binding site was described. One attractive feature of this strategy is the opportunity to tune the selectivity of these inhibitors by systematically varying components. In an extension to this previous work, this study explores the potential of this guided selectivity modulation, leading to a series of inhibitors with different selectivity profiles against highly homologous protein kinase C (PKC) isozymes. Of the inhibitors studied, most exhibited improved potency and selectivity compared with their constituent parts. Furthermore, the selectivity was found to be tunable either through modification of the pseudosubstrate peptide (peptide binding groove) or the ATP-competitive part (ATP binding site). In a number of cases, the selectivity of the construct could be predicted from the initial peptide substrate profiling experiment. Since this strategy is applicable to all kinase sets, it could be used to rapidly develop uniquely selective inhibitors.
authors.affiliation: Medicinal Chemistry and Chemical Biology, Faculty of Science, Utrecht University, Universiteitsweg 99, 3584 CG, Utrecht, The Netherlands.
authors.forename: Loek T M
authors.initials: LT
authors.lastname: van Wandelen
authors.forename: Jeroen
authors.initials: J
authors.lastname: van Ameijde
authors.forename: Ahmed S A
authors.initials: AS
authors.lastname: Mady
authors.forename: Angelique E M
authors.initials: AE
authors.lastname: Wammes
authors.forename: Alois
authors.initials: A
authors.lastname: Bode
authors.forename: Alex J
authors.initials: AJ
authors.lastname: Poot
authors.forename: Rob
authors.initials: R
authors.lastname: Ruijtenbeek
authors.forename: Rob M J
authors.initials: RM
authors.lastname: Liskamp
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D057930:Click Chemistry; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D060327:Solid-Phase Synthesis Techniques; D013379:Substrate Specificity
chemical_list: D007527:Isoenzymes; D010455:Peptides; D047428:Protein Kinase Inhibitors; D000255:Adenosine Triphosphate; D011493:Protein Kinase C