title: Cyclin-dependent kinase inhibition by new C-2 alkynylated purine derivatives and molecular structure of a CDK2-inhibitor complex.
abstract: A new series of 2,6,9-trisubstituted purines, characterized by the presence of a common alkynyl substituent at C-2 and a range of different anilino/benzylamino groups at C-6, were synthesized. These compounds were evaluated for their capacity to inhibit cyclin-dependent kinase activity (CDK1-cyclin B) in vitro. Compounds 4e (N-6-p-Cl-benzylamino derivative) and 5e (N-6-m-Cl-anilino derivative) exhibited the strongest inhibitory activity with an IC(50) of 60 nM. The structure of compound 4b (N-6-p-methoxybenzylamino derivative) in complex with human CDK2 was determined by X-ray crystallography, revealing the molecular basis of inhibition by this molecule. Subsequent molecular modeling studies allowed us to rationalize the SAR observed for these compounds.
authors.affiliation: Section de Recherche, Institut Curie, UMR 176 CNRS, Bât. 110-112, Centre Universitaire, 91405 Orsay Cedex, France. Michel.Legraverend@curie.u-psud.fr
authors.forename: M
authors.initials: M
authors.lastname: Legraverend
authors.forename: P
authors.initials: P
authors.lastname: Tunnah
authors.forename: M
authors.initials: M
authors.lastname: Noble
authors.forename: P
authors.initials: P
authors.lastname: Ducrot
authors.forename: O
authors.initials: O
authors.lastname: Ludwig
authors.forename: D S
authors.initials: DS
authors.lastname: Grierson
authors.forename: M
authors.initials: M
authors.lastname: Leost
authors.forename: L
authors.initials: L
authors.lastname: Meijer
authors.forename: J
authors.initials: J
authors.lastname: Endicott
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry*; D016203:CDC2 Protein Kinase / Q000037:antagonists & inhibitors; D042846:CDC2-CDC28 Kinases; D018360:Crystallography, X-Ray; D019926:Cyclin B / Q000037:antagonists & inhibitors; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011687:Purines / Q000138:chemical synthesis / Q000737:chemistry*; D000077546:Roscovitine; D013329:Structure-Activity Relationship
chemical_list: C461184:1-(6-(3-chlorophenylamino)-9-isopropyl-9H-purin-2-yl)-3-methylpent-1-yn-3-ol; C461183:1-(6-(4-chlorobenzylamino)-9-isopropyl-9H-purin-2-yl)-3-methylpent-1-yn-3-ol; D019926:Cyclin B; D004791:Enzyme Inhibitors; D011687:Purines; D000077546:Roscovitine; 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; D000225:Adenine