Cyclin Dependent Kinase (CDK) Inhibitors

Signal Transduction and Molecular Pharmacology Team

Section: Cancer Research UK Cancer Therapeutics Unit

Inhibitors of CDKs are important drug candidates because of their potential to restore the inhibitory control of the cell cycle that is frequently lost in cancer cells. In addition, they may also induce apoptosis via the deregulated E2F1 transcription factor. We have already published the results of a detailed investigation of the molecular mechanism of action of R-roscovitine (CYC202), which has completed clinical trial at our institution.

We demonstrated decreased retinoblastoma protein (RB) phosphorylation, consistent with CDK inhibition, and a number of other interesting molecular effects, including activation of the MEK to ERK1/2 pathway and reduced expression of cyclin D1. We have shown that the efficacy of CYC202 is likely to be due to the combined inhibition of CDK2 together with the transcriptional kinases CDK7,8,9 leading to reduced RNA polymerase phosphorylation and decreased expression of cyclins.

This provides a combinatorial blockade of RB phosphorylation that is more effective than inhibition of CDK2 alone. We extended our work to establish detailed pharmacokinetic-pharmacodynamic relationships in human tumour xenograft models. Using gene expression microarray analysis, we have shown downregulation of genes involved in progression through mitosis. Mechanistic effects have been demonstrated with new CDK inhibitors synthesised in-house that exhibit enhanced potency and pharmacokinetic properties. The molecular mode of action of cell cycle inhibitors with a novel mechanism of action continues to be characterised.