title: Discovery of a potent CDK2 inhibitor with a novel binding mode, using virtual screening and initial, structure-guided lead scoping.
abstract: Virtual screening against a pCDK2/cyclin A crystal structure led to the identification of a potent and novel CDK2 inhibitor, which exhibited an unusual mode of interaction with the kinase binding motif. With the aid of X-ray crystallography and modelling, a medicinal chemistry strategy was implemented to probe the interactions seen in the crystal structure and to establish SAR. A fragment-based approach was also considered but a different, more conventional, binding mode was observed. Compound selectivity against GSK-3beta was improved using a rational design strategy, with crystallographic verification of the CDK2 binding mode.
authors.affiliation: Vernalis (R&D) Ltd, Granta Park, Cambridge CB21 6GB, UK. c.richardson@vernalis.com
authors.forename: Christine M
authors.initials: CM
authors.lastname: Richardson
authors.forename: Claire L
authors.initials: CL
authors.lastname: Nunns
authors.forename: Douglas S
authors.initials: DS
authors.lastname: Williamson
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Parratt
authors.forename: Pawel
authors.initials: P
authors.lastname: Dokurno
authors.forename: Rob
authors.initials: R
authors.lastname: Howes
authors.forename: Jenifer
authors.initials: J
authors.lastname: Borgognoni
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Drysdale
authors.forename: Harry
authors.initials: H
authors.lastname: Finch
authors.forename: Roderick E
authors.initials: RE
authors.lastname: Hubbard
authors.forename: Philip S
authors.initials: PS
authors.lastname: Jackson
authors.forename: Peter
authors.initials: P
authors.lastname: Kierstan
authors.forename: Georg
authors.initials: G
authors.lastname: Lentzen
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Moore
authors.forename: James B
authors.initials: JB
authors.lastname: Murray
authors.forename: Heather
authors.initials: H
authors.lastname: Simmonite
authors.forename: Allan E
authors.initials: AE
authors.lastname: Surgenor
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Torrance
mesh_terms: D018360:Crystallography, X-Ray; D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors*; D015195:Drug Design; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D047428:Protein Kinase Inhibitors; D051357:Cyclin-Dependent Kinase 2