title: Cyclin-Dependent Kinase (CDK) Inhibitors: Structure-Activity Relationships and Insights into the CDK-2 Selectivity of 6-Substituted 2-Arylaminopurines.
abstract: Purines and related heterocycles substituted at C-2 with 4'-sulfamoylanilino and at C-6 with a variety of groups have been synthesized with the aim of achieving selectivity of binding to CDK2 over CDK1. 6-Substituents that favor competitive inhibition at the ATP binding site of CDK2 were identified and typically exhibited 10-80-fold greater inhibition of CDK2 compared to CDK1. Most impressive was 4-((6-([1,1'-biphenyl]-3-yl)-9H-purin-2-yl)amino) benzenesulfonamide (73) that exhibited high potency toward CDK2 (IC500.044 μM) but was ∼2000-fold less active toward CDK1 (IC5086 μM). This compound is therefore a useful tool for studies of cell cycle regulation. Crystal structures of inhibitor-kinase complexes showed that the inhibitor stabilizes a glycine-rich loop conformation that shapes the ATP ribose binding pocket and that is preferred in CDK2 but has not been observed in CDK1. This aspect of the active site may be exploited for the design of inhibitors that distinguish between CDK1 and CDK2.
authors.affiliation: Newcastle Cancer Centre, Northern Institute for Cancer Research, School of Chemistry, Newcastle University , Bedson Building, Newcastle upon Tyne NE1 7RU, U.K.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Coxon
authors.affiliation: Department of Biochemistry, University of Oxford , South Parks Road, Oxford, OX1 3QU, U.K.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Anscombe
authors.affiliation: Newcastle Cancer Centre, Northern Institute for Cancer Research, School of Chemistry, Newcastle University , Bedson Building, Newcastle upon Tyne NE1 7RU, U.K.
authors.forename: Suzannah J
authors.identifier: 0000-0003-1646-593X
authors.initials: SJ
authors.lastname: Harnor
authors.affiliation: Newcastle Cancer Centre, Northern Institute for Cancer Research, Newcastle University Medical School , Paul O'Gorman Building, Framlington Place, Newcastle upon Tyne, NE2 4HH, U.K.
authors.forename: Mathew P
authors.initials: MP
authors.lastname: Martin
authors.affiliation: Newcastle Cancer Centre, Northern Institute for Cancer Research, School of Chemistry, Newcastle University , Bedson Building, Newcastle upon Tyne NE1 7RU, U.K.
authors.forename: Benoit
authors.initials: B
authors.lastname: Carbain
authors.affiliation: Newcastle Cancer Centre, Northern Institute for Cancer Research, School of Chemistry, Newcastle University , Bedson Building, Newcastle upon Tyne NE1 7RU, U.K.
authors.forename: Bernard T
authors.initials: BT
authors.lastname: Golding
authors.affiliation: Newcastle Cancer Centre, Northern Institute for Cancer Research, School of Chemistry, Newcastle University , Bedson Building, Newcastle upon Tyne NE1 7RU, U.K.
authors.forename: Ian R
authors.initials: IR
authors.lastname: Hardcastle
authors.affiliation: Newcastle Cancer Centre, Northern Institute for Cancer Research, School of Chemistry, Newcastle University , Bedson Building, Newcastle upon Tyne NE1 7RU, U.K.
authors.forename: Lisa K
authors.initials: LK
authors.lastname: Harlow
authors.affiliation: Newcastle Cancer Centre, Northern Institute for Cancer Research, Newcastle University Medical School , Paul O'Gorman Building, Framlington Place, Newcastle upon Tyne, NE2 4HH, U.K.
authors.forename: Svitlana
authors.initials: S
authors.lastname: Korolchuk
authors.affiliation: Newcastle Cancer Centre, Northern Institute for Cancer Research, School of Chemistry, Newcastle University , Bedson Building, Newcastle upon Tyne NE1 7RU, U.K.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Matheson
authors.affiliation: Newcastle Cancer Centre, Northern Institute for Cancer Research, Newcastle University Medical School , Paul O'Gorman Building, Framlington Place, Newcastle upon Tyne, NE2 4HH, U.K.
authors.forename: David R
authors.initials: DR
authors.lastname: Newell
authors.affiliation: Department of Biochemistry, University of Oxford , South Parks Road, Oxford, OX1 3QU, U.K.
authors.forename: Martin E M
authors.initials: ME
authors.lastname: Noble
authors.affiliation: Newcastle Cancer Centre, Northern Institute for Cancer Research, School of Chemistry, Newcastle University , Bedson Building, Newcastle upon Tyne NE1 7RU, U.K.
authors.forename: Mangaleswaran
authors.initials: M
authors.lastname: Sivaprakasam
authors.affiliation: Newcastle Cancer Centre, Northern Institute for Cancer Research, Newcastle University Medical School , Paul O'Gorman Building, Framlington Place, Newcastle upon Tyne, NE2 4HH, U.K.
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Tudhope
authors.affiliation: Newcastle Cancer Centre, Northern Institute for Cancer Research, School of Chemistry, Newcastle University , Bedson Building, Newcastle upon Tyne NE1 7RU, U.K.
authors.forename: David M
authors.initials: DM
authors.lastname: Turner
authors.affiliation: Newcastle Cancer Centre, Northern Institute for Cancer Research, Newcastle University Medical School , Paul O'Gorman Building, Framlington Place, Newcastle upon Tyne, NE2 4HH, U.K.
authors.forename: Lan Z
authors.initials: LZ
authors.lastname: Wang
authors.affiliation: Newcastle Cancer Centre, Northern Institute for Cancer Research, Newcastle University Medical School , Paul O'Gorman Building, Framlington Place, Newcastle upon Tyne, NE2 4HH, U.K.
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Wedge
authors.affiliation: Newcastle Cancer Centre, Northern Institute for Cancer Research, School of Chemistry, Newcastle University , Bedson Building, Newcastle upon Tyne NE1 7RU, U.K.
authors.forename: Christopher
authors.initials: C
authors.lastname: Wong
authors.affiliation: Newcastle Cancer Centre, Northern Institute for Cancer Research, School of Chemistry, Newcastle University , Bedson Building, Newcastle upon Tyne NE1 7RU, U.K.
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Griffin
authors.affiliation: Department of Biochemistry, University of Oxford , South Parks Road, Oxford, OX1 3QU, U.K.
authors.forename: Jane A
authors.initials: JA
authors.lastname: Endicott
authors.affiliation: Newcastle Cancer Centre, Northern Institute for Cancer Research, School of Chemistry, Newcastle University , Bedson Building, Newcastle upon Tyne NE1 7RU, U.K.
authors.forename: Céline
authors.identifier: 0000-0002-2032-2272
authors.initials: C
authors.lastname: Cano
mesh_terms: D018360:Crystallography, X-Ray; D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors*; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D011687:Purines / Q000494:pharmacology*; D013057:Spectrum Analysis / Q000379:methods; D013329:Structure-Activity Relationship
chemical_list: D047428:Protein Kinase Inhibitors; D011687:Purines; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2