title: Structure-based design of a potent purine-based cyclin-dependent kinase inhibitor.
abstract: Aberrant control of cyclin-dependent kinases (CDKs) is a central feature of the molecular pathology of cancer. Iterative structure-based design was used to optimize the ATP- competitive inhibition of CDK1 and CDK2 by O(6)-cyclohexylmethylguanines, resulting in O(6)-cyclohexylmethyl-2-(4'- sulfamoylanilino)purine. The new inhibitor is 1,000-fold more potent than the parent compound (K(i) values for CDK1 = 9 nM and CDK2 = 6 nM versus 5,000 nM and 12,000 nM, respectively, for O(6)-cyclohexylmethylguanine). The increased potency arises primarily from the formation of two additional hydrogen bonds between the inhibitor and Asp 86 of CDK2, which facilitate optimum hydrophobic packing of the anilino group with the specificity surface of CDK2. Cellular studies with O(6)-cyclohexylmethyl-2-(4'- sulfamoylanilino) purine demonstrated inhibition of MCF-7 cell growth and target protein phosphorylation, consistent with CDK1 and CDK2 inhibition. The work represents the first successful iterative synthesis of a potent CDK inhibitor based on the structure of fully activated CDK2-cyclin A. Furthermore, the potency of O(6)-cyclohexylmethyl-2-(4'- sulfamoylanilino)purine was both predicted and fully rationalized on the basis of protein-ligand interactions.
authors.affiliation: Laboratory of Molecular Biophysics and Department of Biochemistry, University of Oxford, Oxford, OX1 3QU, UK.
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Davies
authors.forename: Johanne
authors.initials: J
authors.lastname: Bentley
authors.forename: Christine E
authors.initials: CE
authors.lastname: Arris
authors.forename: F Thomas
authors.initials: FT
authors.lastname: Boyle
authors.forename: Nicola J
authors.initials: NJ
authors.lastname: Curtin
authors.forename: Jane A
authors.initials: JA
authors.lastname: Endicott
authors.forename: Ashleigh E
authors.initials: AE
authors.lastname: Gibson
authors.forename: Bernard T
authors.initials: BT
authors.lastname: Golding
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Griffin
authors.forename: Ian R
authors.initials: IR
authors.lastname: Hardcastle
authors.forename: Philip
authors.initials: P
authors.lastname: Jewsbury
authors.forename: Louise N
authors.initials: LN
authors.lastname: Johnson
authors.forename: Veronique
authors.initials: V
authors.lastname: Mesguiche
authors.forename: David R
authors.initials: DR
authors.lastname: Newell
authors.forename: Martin E M
authors.initials: ME
authors.lastname: Noble
authors.forename: Julie A
authors.initials: JA
authors.lastname: Tucker
authors.forename: Lan
authors.initials: L
authors.lastname: Wang
authors.forename: Hayley J
authors.initials: HJ
authors.lastname: Whitfield
mesh_terms: D016203:CDC2 Protein Kinase / Q000037:antagonists & inhibitors*; D042846:CDC2-CDC28 Kinases; D019925:Cyclin A / Q000378:metabolism*; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D006147:Guanine / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011687:Purines / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D019925:Cyclin A; D004791:Enzyme Inhibitors; C466913:NU2058; C466914:NU6102; D011687:Purines; D006147:Guanine; D017346:Protein Serine-Threonine Kinases; D016203:CDC2 Protein Kinase; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases