title: Fascaplysin-inspired diindolyls as selective inhibitors of CDK4/cyclin D1.
abstract: We present the design, synthesis and biological activity of a new series of substituted 3-(2-(1H-indol-1-yl)ethyl)-1H-indoles and 1,2-di(1H-indol-1-yl)alkanes as selective inhibitors of CDK4/cyclin D1. The compounds were designed to explore the relationship between the connection mode of the indolyl moieties and their CDK inhibitory activities. We found all the above-mentioned designed compounds to be selective inhibitors of CDK4/cyclin D1 compared to the closely related CDK2/cyclin A, with IC(50) for the best compounds 10m and 13a being 39 and 37microm, respectively.
authors.affiliation: Department of Chemistry, University of Leicester, UK.
authors.forename: Carine
authors.initials: C
authors.lastname: Aubry
authors.forename: A James
authors.initials: AJ
authors.lastname: Wilson
authors.forename: Daniel
authors.initials: D
authors.lastname: Emmerson
authors.forename: Emma
authors.initials: E
authors.lastname: Murphy
authors.forename: Yu Yam
authors.initials: YY
authors.lastname: Chan
authors.forename: Michael P
authors.initials: MP
authors.lastname: Dickens
authors.forename: Marcos D
authors.initials: MD
authors.lastname: García
authors.forename: Paul R
authors.initials: PR
authors.lastname: Jenkins
authors.forename: Sachin
authors.initials: S
authors.lastname: Mahale
authors.forename: Bhabatosh
authors.initials: B
authors.lastname: Chaudhuri
mesh_terms: D001665:Binding Sites; D003198:Computer Simulation; D019925:Cyclin A / Q000037:antagonists & inhibitors / Q000378:metabolism; D019938:Cyclin D1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D051358:Cyclin-Dependent Kinase 4 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015195:Drug Design; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000644:Quaternary Ammonium Compounds; D002243:Carbolines; D007212:Indolizines
chemical_list: D019925:Cyclin A; D019938:Cyclin D1; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D007211:Indoles; D047428:Protein Kinase Inhibitors; C544486:1,2-bis-(indol-1-yl)-ethane; C544485:5-chloro-3-(2-(5-chloro-3a,7a-dihydro-indol-1-yl)-ethyl)-1H-indole; C069346:fascaplysine; D000644:Quaternary Ammonium Compounds; D002243:Carbolines; D007212:Indolizines