title: 3,5,6-Trisubstituted naphthostyrils as CDK2 inhibitors.
abstract: A novel class of 3,5,6-trisubstituted naphthostyril analogues was designed and synthesized to study the structure-activity relationship for inhibition of cyclin-dependent kinase 2 (CDK2). These compounds, particularly molecules with side-chain modifications providing additional hydrogen bonding capability, were demonstrated to be potent CDK2 inhibitors with cellular activities consistent with CDK2 inhibition. These molecules inhibited tumor cell proliferation and G1-S and G2-M cell-cycle progression in vitro. The X-ray crystal structure of a 2-aminoethyleneamine derivative bound to CDK2, refined to 2.5A resolution, is presented.
authors.affiliation: Department of Discovery Chemistry, Hoffmann-La Roche Inc., 340 Kingsland Street, Nutley, NJ 07110, USA. jin-jin.liu@roche.com
authors.forename: Jin-Jun
authors.initials: JJ
authors.lastname: Liu
authors.forename: Apostolos
authors.initials: A
authors.lastname: Dermatakis
authors.forename: Christine
authors.initials: C
authors.lastname: Lukacs
authors.forename: Fred
authors.initials: F
authors.lastname: Konzelmann
authors.forename: Yi
authors.initials: Y
authors.lastname: Chen
authors.forename: Ursula
authors.initials: U
authors.lastname: Kammlott
authors.forename: Wanda
authors.initials: W
authors.lastname: Depinto
authors.forename: Hong
authors.initials: H
authors.lastname: Yang
authors.forename: Xuefeng
authors.initials: X
authors.lastname: Yin
authors.forename: Yingsi
authors.initials: Y
authors.lastname: Chen
authors.forename: Andy
authors.initials: A
authors.lastname: Schutt
authors.forename: Mary Ellen
authors.initials: ME
authors.lastname: Simcox
authors.forename: Kin-Chun
authors.initials: KC
authors.lastname: Luk
mesh_terms: D000963:Antimetabolites; D001973:Bromodeoxyuridine; D042846:CDC2-CDC28 Kinases / Q000037:antagonists & inhibitors*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D051357:Cyclin-Dependent Kinase 2; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D006801:Humans; D007202:Indicators and Reagents; D008958:Models, Molecular; D008968:Molecular Conformation; D009281:Naphthalenes / Q000138:chemical synthesis* / Q000494:pharmacology*; D010084:Oxidation-Reduction; D011758:Pyrroles / Q000138:chemical synthesis* / Q000494:pharmacology*; D013778:Tetrazolium Salts; D013844:Thiazoles
chemical_list: D000963:Antimetabolites; D004791:Enzyme Inhibitors; D007202:Indicators and Reagents; D009281:Naphthalenes; D011758:Pyrroles; D013778:Tetrazolium Salts; D013844:Thiazoles; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; C022616:thiazolyl blue; D001973:Bromodeoxyuridine