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Fascaplysin-inspired diindolyls as selective inhibitors of CDK4/cyclin D1.

Aubry, Carine; Wilson, A James; Emmerson, Daniel; Murphy, Emma; Chan, Yu Yam; Dickens, Michael P; García, Marcos D; Jenkins, Paul R; Mahale, Sachin; Chaudhuri, Bhabatosh.

Bioorg Med Chem ; 17(16): 6073-84, 2009 Aug 15.

Article in English | MEDLINE | ID: mdl-19632122

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.

Subject(s)

Cyclin D1/antagonists & inhibitors , Cyclin-Dependent Kinase 4/antagonists & inhibitors , Indoles/chemistry , Protein Kinase Inhibitors/chemistry , Binding Sites , Computer Simulation , Cyclin A/antagonists & inhibitors , Cyclin A/metabolism , Cyclin D1/metabolism , Cyclin-Dependent Kinase 2/antagonists & inhibitors , Cyclin-Dependent Kinase 2/metabolism , Cyclin-Dependent Kinase 4/metabolism , Drug Design , Humans , Indoles/chemical synthesis , Indoles/pharmacology , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacology

ABSTRACT

Subject(s)

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