Discovery of a potent CDK2 inhibitor with a novel binding mode, using virtual screening and initial, structure-guided lead scoping.
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.
Richardson
Christine M
CM
Vernalis (R&D) Ltd, Granta Park, Cambridge CB21 6GB, UK. c.richardson@vernalis.com
Nunns
Claire L
CL
Williamson
Douglas S
DS
Parratt
Martin J
MJ
Dokurno
Pawel
P
Howes
Rob
R
Borgognoni
Jenifer
J
Drysdale
Martin J
MJ
Finch
Harry
H
Hubbard
Roderick E
RE
Jackson
Philip S
PS
Kierstan
Peter
P
Lentzen
Georg
G
Moore
Jonathan D
JD
Murray
James B
JB
Simmonite
Heather
H
Surgenor
Allan E
AE
Torrance
Christopher J
CJ
D018360:Crystallography, X-Ray; D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors*; D015195:Drug Design; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*
D047428:Protein Kinase Inhibitors; D051357:Cyclin-Dependent Kinase 2