Irreversible Molecular Glues to Activate Anti-Cancer Interactome of 14-3-3sigma

The need for new medicines is greater than ever, in large part due to the UK ageing population and the complex clinical challenges brought about by drug resistance and/or side effects. These problems are particularly acute in the oncology therapeutic area and have a significant negative impacts on society and the economy. This project will initiate and accelerate the development of a new class of medicines that will revolutionise pharmaceutical development.

Many diseases, and in particular cancer, result from dysregulation of a network of interacting proteins. Disrupting the resulting 'bad' lines of communication by inhibiting certain protein-protein interactions is a challenging but transformative therapeutic approach to have emerged over recent years. This has led to promising new drugs such as Venetoclax which has recently been approved for the treatment of lymphocytic leukaemia. However, as patient numbers continue to increase and drug resistance grows, the need for new cancer medicines and therapeutic strategies remains acute.

This project will directly address this need by taking the opposite and novel approach of stabilising 'good' protein-protein interactions that promote the body's fight against cancer. Drugs that achieve this by binding to the interface of two proteins can be thought of as 'molecular glues'. This strategy has enormous potential because it can unlock a plethora of new ways to treat disease. It has been under-exploited in drug discovery because simultaneously targeting two proteins at their interface is highly challenging owing to the complex mechanics involved. The potential impact has not gone unnoticed however, and there is now growing interest in 'molecular glues' from the pharmaceutical sector following recent advances.

My work in this area has focussed on developing molecular glues that stabilise interactions of an important family of communication hub proteins called 14-3-3. 14-3-3 interactions with other proteins represent novel intervention points that can be used to develop new treatments for diseases such as Parkinson's disease, cystic fibrosis and cancer. In particular a single family member called 14-3-3sigma exhibits unique behaviour and plays an important role in stopping cancer cell growth. My group has recently discovered a way to specifically target this family member.

Building on exciting preliminary findings, this project will target two 14-3-3sigma PPIs that are critical to our body's fight against cancer: those with ERa, which drives breast cancer development, and p53, the most important tumour suppressor. In both cases molecular glues that stabilise the interactions with 14-3-3sigma have the potential to be effective anti-cancer drugs that have a unique mode of action, and have the potential for precision delivery to cancer tissue.

This will be achieved through a unique research programme that pioneers cutting edge chemical and biological methodology to engineer molecular glues with differing specifications. These glues are unique and will be particularly effective because they permanently (or irreversibly) bind to the 14-3-3sigma protein. There are three objectives:

1. Build on the preliminary data to design, synthesise and evaluate potent irreversible molecular glues that specifically target the 14-3-3sigma isoform using a comprehensive analytical workflow.
2. Design and synthesise partner-protein specific selective and photoactivatable tethered glues that can be specifically activated in tumours using light.
3. Show that irreversible molecular glues are effective anti-cancer agents through cancer cell-based experiments, paving the way for clinical translation of targeted therapies.

These innovative molecular glues will impact on global pharmaceutical research and development by accelerating the maturation of 14-3-3 as a powerful drug target, initiating clinical translation and demonstrating the wider potential of molecular glues as medicines.