Discovery of a potent CDK2 inhibitor with a novel binding mode, using virtual screening and initial, structure-guided lead scoping

…, MJ Parratt, P Dokurno, R Howes, J Borgognoni…

Index: Richardson, Christine M.; Nunns, Claire L.; Williamson, Douglas S.; Parratt, Martin J.; Dokurno, Pawel; Howes, Rob; Borgognoni, Jenifer; Drysdale, Martin J.; Finch, Harry; Hubbard, Roderick E.; Jackson, Philip S.; Kierstan, Peter; Lentzen, Georg; Moore, Jonathan D.; Murray, James B.; Simmonite, Heather; Surgenor, Allan E.; Torrance, Christopher J. Bioorganic and Medicinal Chemistry Letters, 2007 , vol. 17, # 14 p. 3880 - 3885

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Citation Number: 35

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, ...