title: Structure-aided optimization of kinase inhibitors derived from alsterpaullone.
abstract: In order to perform computer-aided design of novel alsterpaullone derivatives, the vicinity of the entrance to the ATP-binding site was scanned for areas that could be useful as anchoring points for additional protein-ligand interactions. Based on the alignment of alsterpaullone in a CDK1/cyclin B homology model, substituents were attached to the 2-position of the parent scaffold to enable contacts within the identified areas. Synthesis of the designed structures revealed three derivatives (3-5) with kinase-inhibitory activity similar to alsterpaullone. The novel 2-cyanoethylalsterpaullone (7) proved to be the most potent paullone described so far, exhibiting inhibitory concentrations for CDK1/ cyclin B and GSK-3beta in the picomolar range.
authors.affiliation: Institut für Pharmazeutische Chemie, Technische Universität Braunschweig, Beethovenstrasse 55, 38106 Braunschweig, Germany. c.kunick@tu-bs.de
authors.forename: Conrad
authors.initials: C
authors.lastname: Kunick
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Zeng
authors.forename: Rick
authors.initials: R
authors.lastname: Gussio
authors.forename: Daniel
authors.initials: D
authors.lastname: Zaharevitz
authors.forename: Maryse
authors.initials: M
authors.lastname: Leost
authors.forename: Frank
authors.initials: F
authors.lastname: Totzke
authors.forename: Christoph
authors.initials: C
authors.lastname: Schächtele
authors.forename: Michael H G
authors.initials: MH
authors.lastname: Kubbutat
authors.forename: Laurent
authors.initials: L
authors.lastname: Meijer
authors.forename: Thomas
authors.initials: T
authors.lastname: Lemcke
mesh_terms: D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D001552:Benzazepines / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D016203:CDC2 Protein Kinase / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D002460:Cell Line; D015195:Drug Design; D007211:Indoles / Q000737:chemistry* / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D008968:Molecular Conformation; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D018411:Spodoptera; D013329:Structure-Activity Relationship
chemical_list: D001552:Benzazepines; D007211:Indoles; D047428:Protein Kinase Inhibitors; C120793:alsterpaullone; D000255:Adenosine Triphosphate; D016203:CDC2 Protein Kinase