Evaluation of transcriptional cyclin dependent kinase inhibitors as potential cancer therapeutics
Liu, Xiangrui (2012) Evaluation of transcriptional cyclin dependent kinase inhibitors as potential cancer therapeutics. PhD thesis, University of Nottingham.
Cancer cells depend heavily on sustained expression of anti-apoptotic proteins. Targeting transcription to suppress these anti-apoptotic proteins seems a promising strategy for anti-cancer therapy. Cyclin-dependant kinase 9 (CDK9) regulates transcription elongation by phosphorylating Ser2 on the C-terminal domain of RNA polymerase II, while CDK7 phosphorylates Ser5 during transcription initiation. A screening cascade comprised of an MTT assay, a caspase-3 activation assay, a p53 stabilization assay and a mitotic index assay was developed to classify compounds and identify lead transcriptional CDK inhibitors from a novel class of 2,4,5-trisubstituted pyrimidines. Compounds S3-41 and CDKI-71 are the most potent CDK9 inhibitors identified by the screening cascade. They showed potent anti-proliferative activity in the MTT assay and induce both caspase-3 activity and p53 protein level at the GI50 concentration. In addition, no significant effect on mitotic index was observed.
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