Fascaplysin-inspired diindolyls as selective inhibitors of CDK4/cyclin D1.
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.
Aubry
Carine
C
Department of Chemistry, University of Leicester, UK.
Wilson
A James
AJ
Emmerson
Daniel
D
Murphy
Emma
E
Chan
Yu Yam
YY
Dickens
Michael P
MP
García
Marcos D
MD
Jenkins
Paul R
PR
Mahale
Sachin
S
Chaudhuri
Bhabatosh
B
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
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