title: 6-Cyclohexylmethoxy-5-(cyano-NNO-azoxy)pyrimidine-4-amine: a new scaffold endowed with potent CDK2 inhibitory activity.
abstract: Substitution of the cyano-NNO-azoxy moiety (NC-N=(O)N-) for the nitroso group in NU6027, a potent and selective CDK2 inhibitor, affords a compound with slightly improved potency and comparable selectivity profile. A molecular modelling study indicates for this new scaffold a binding mode similar to the one adopted by other purine and pyrimidine analogues, and suggests a relevant role for a conserved water molecule in stabilizing the bioactive pose of this and other pyrimidine ligands. The introduction of aminosulfonylphenyl substituents on the 2-amino group of the pyrimidine increased the CDK2 inhibitory potency by two orders of magnitude, while maintaining the same degree of selectivity.
authors.affiliation: Dipartimento di Scienza e Tecnologia del Farmaco, Università degli Studi di Torino, via Pietro Giuria 9, 10125 Torino, Italy.
authors.forename: Donatella
authors.initials: D
authors.lastname: Boschi
authors.forename: Paolo
authors.initials: P
authors.lastname: Tosco
authors.forename: Naveen
authors.initials: N
authors.lastname: Chandra
authors.forename: Shilpi
authors.initials: S
authors.lastname: Chaurasia
authors.forename: Roberta
authors.initials: R
authors.lastname: Fruttero
authors.forename: Roger
authors.initials: R
authors.lastname: Griffin
authors.forename: Lan-Zhen
authors.initials: LZ
authors.lastname: Wang
authors.forename: Alberto
authors.initials: A
authors.lastname: Gasco
mesh_terms: D000588:Amines / Q000737:chemistry* / Q000494:pharmacology*; D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors*; D004789:Enzyme Activation / Q000187:drug effects; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000588:Amines; D047428:Protein Kinase Inhibitors; D051357:Cyclin-Dependent Kinase 2
keywords: 5-Substituted pyrimidine-4-amine; CDK inhibitor; CDK2 selective inhibitor; Cyano-NNO-azoxy; Water-mediated hydrogen bond