title: 8-Substituted O(6)-cyclohexylmethylguanine CDK2 inhibitors: using structure-based inhibitor design to optimize an alternative binding mode.
abstract: Evaluation of the effects of purine C-8 substitution within a series of CDK1/2-selective O(6)-cyclohexylmethylguanine derivatives revealed that potency decreases initially with increasing size of the alkyl substituent. Structural analysis showed that C-8 substitution is poorly tolerated, and to avoid unacceptable steric interactions, these compounds adopt novel binding modes. Thus, 2-amino-6-cyclohexylmethoxy-8-isopropyl-9H-purine adopts a "reverse" binding mode where the purine backbone has flipped 180°. This provided a novel lead chemotype from which we have designed more potent CDK2 inhibitors using, in the first instance, quantum mechanical energy calculations. Introduction of an ortho-tolyl or ortho-chlorophenyl group at the purine C-8 position restored the potency of these "reverse" binding mode inhibitors to that of the parent 2-amino-6-cyclohexylmethoxy-9H-purine. By contrast, the corresponding 8-(2-methyl-3-sulfamoylphenyl)-purine derivative exhibited submicromolar CDK2-inhibitory activity by virtue of engineered additional interactions with Asp86 and Lys89 in the reversed binding mode, as confirmed by X-ray crystallography.
authors.affiliation: Department of Biochemistry, University of Oxford , South Parks Road, Oxford OX1 3QU, U.K.
authors.forename: Benoit
authors.initials: B
authors.lastname: Carbain
authors.forename: David J
authors.initials: DJ
authors.lastname: Paterson
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Anscombe
authors.forename: Allyson J
authors.initials: AJ
authors.lastname: Campbell
authors.forename: Celine
authors.initials: C
authors.lastname: Cano
authors.forename: Aude
authors.initials: A
authors.lastname: Echalier
authors.forename: Jane A
authors.initials: JA
authors.lastname: Endicott
authors.forename: Bernard T
authors.initials: BT
authors.lastname: Golding
authors.forename: Karen
authors.initials: K
authors.lastname: Haggerty
authors.forename: Ian R
authors.initials: IR
authors.lastname: Hardcastle
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Jewsbury
authors.forename: David R
authors.initials: DR
authors.lastname: Newell
authors.forename: Martin E M
authors.initials: ME
authors.lastname: Noble
authors.forename: Celine
authors.initials: C
authors.lastname: Roche
authors.forename: Lan Z
authors.initials: LZ
authors.lastname: Wang
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Griffin
mesh_terms: D001665:Binding Sites; D018360:Crystallography, X-Ray; D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors*; D015195:Drug Design; D008958:Models, Molecular; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: D047428:Protein Kinase Inhibitors; D051357:Cyclin-Dependent Kinase 2