A multi-disciplinary research team from the MRC Laboratory of Molecular Biology, the Universities of Oxford (TDI Kessler group), Liverpool, Cancer Research UK and Forma Therapeutics has focused on another component of the system, USP7. This controls the stability of a protein called p53 that is lost in many cancer types. p53 is critical for controlling cell growth. USP7 inhibition elevates levels of p53 and interferes with cancer cell proliferation. Chemists at Forma obtained potent and selective inhibitors against USP7, which are supported by elegant structural work at atomic resolution, detailing how the drug binds to its target.
USP7 is a member of a family of proteins called deubiquitylating enzymes (DUBs), and it has been unclear whether it would be possible to design drugs that are selective for just one member of the DUB family.“We show not only that this is possible, but our structures provide a detailed understanding of how this is achieved“ says Dr. Andrew Turnbull of CRUK’s Therapeutic Discovery Labs, one of the lead authors of the study. Extending the approach to other family members will open up ways to target other previously “undruggable”proteins which drive cancer, or in fact other chronic diseases such as neurodegeneration and immunological disorders.
- Novel ways to manipulate "undruggable" targets in oncology
- Proteostasis of tumour oncogenes and tumour suppressor genes
- Ubiquitin-proteasome system in drug discovery
- First structure based design of selective USP7 inhibitors with anti-tumor effects in mice