A new approach to targeting key cancer-linked proteins, thought to be ‘undruggable’, has been discovered through an alliance between industry and academia created by Cancer Research UK.
The results of the study, published in Nature*, show that two novel and specific small-molecule inhibitors developed by the alliance can bind to and deactivate an enzyme that controls the stability of the p53 tumour suppressor protein. This deactivation allows p53 to be turned on, putting the brakes on cancer growth.
The four year multidisciplinary research collaboration was brought together by Cancer Research UK’s Therapeutic Discovery Laboratories and includes scientists at FORMA Therapeutics Inc (USA), the Universities of Oxford and Liverpool, and the MRC Laboratory for Molecular Biology in Cambridge.
The majority of cancers have a faulty or inactive p53 which allows them grow out of control. But despite its important role in cancer, attempts to target p53 directly have hit a number of dead ends. To get around this problem the researchers in this alliance looked at a specialised system, the ubiquitin-proteasome system, which regulates the turnover of a range of proteins, including p53.
Focusing on one enzyme in the system, USP7, the researchers were able to show how the two inhibitors exploit a unique binding site in the enzyme. This leads to a cascade of effects that ultimately reactivate p53.
Dr Andrew Turnbull, one of the lead researchers at the Cancer Research UK Therapeutic Discovery Laboratories, said: “Our study shows that we can target these ‘undruggable’ proteins by specifically targeting the enzymes that control them. Combining this revelation with detailed three-dimensional structures of these enzymes, and their potential targets, means this could be the starting point to develop drugs that target them and the proteins they control.”
Dr Tim Hammonds, deputy director of Cancer Research UK’s Therapeutic Discovery Laboratories, said: “Our alliance model of bringing together the best academics, our own laboratories and leading industry partners means that we can take novel and bold approaches to tackling some of the biggest challenges in cancer. Enabling experts to collaborate, with the freedom to explore the full breadth of a problem and multiple drug targets, engenders creativity and new academic discoveries as we work to develop potential new cancer drugs.”
*Turnbull, A., et al Molecular basis of USP7 inhibition by selective small molecule inhibitors Nature (2017). DOI: 10.1038/nature24451