Discovery and profiling of small-molecule inhibitors of cellular nuclease enzymes

Nuclease enzymes are non-traditional drug targets that attract an increasing amount of interest as potential targets relevant for a variety of therapeutic areas including infection, cancer and bone disease. A case in point is the Ccr4-Not complex, which contains two nuclease subunits (Caf1 and Ccr4) that are involved in the degradation of the poly(A) tail of cytoplasmic mRNA. Pharmacological inhibition of this nuclease complex may have therapeutic benefit by enhancing bone mass and reducing the metastatic potential of breast cancer cells.
The aim of the project is to (i) characterise our compounds targeting the Caf1 subunit by biochemical and cellular profiling, and (ii) discover new compound that inhibit the second catalytic subunit Ccr4.
This project will build on our work on: (i) the discovery of drug-like inhibitors of Caf1; (ii) the development and validation of various biochemical assays to evaluate enzyme activity and inhibitor binding using fluorescence and chemiluminescence-based techniques; and (iii) cell-based techniques to evaluate the activity of Ccr4-Not components.
This project provides opportunities to obtain experience with a range of techniques, including recombinant protein expression, enzyme assays, compound screening, cell culture and quantitative analysis. These skills are highly relevant for drug discovery and an excellent preparation for a variety of careers in academia or industry.