A Cellular Screen for Inhibitors of pRB Phosphorylation

Cell Cycle Control Team

Section: Cancer Research UK Cancer Therapeutics Unit

Another aspect of our work follows from the opportunity to participate in the development of drug screens for cancer targets. An example of this is the cell-based screen for inhibitors of pRB phosphorylation. Phosphorylation of the tumour suppressor protein pRB during G1 by cyclin-dependent kinases is essential for G1 progression, and most human cancers contain genetic alterations in at least one member of this pathway, leading to inappropriate phosphorylation and deregulation of pRB activity. We have therefore developed a high-throughput cellular assay to screen for small molecules that inhibit pRB phosphorylation. A pilot screen of 2,000 compounds and a screen of the full compound library have been successfully completed using this assay. These screens have led to the identification of a number of cell-permeable small molecules that inhibit pRB phosphorylation. Our efforts are now focussing on identifying the cellular target for each of these small molecules and also evaluating their potential for future drug development.