Jessica Hurcum

Novel approaches for the identification of allosteric inhibitors of high value therapeutic targets (CASE)

About me

Throughout my time studying at the University of Sussex where I obtained a MSci, I had the opportunity to undertake three very diverse projects. In my second year I was involved in a project as a Junior Research Associate in the Cox laboratory developing a library of compounds based of 2,4-methanoproline derivative to be screened for the treatment of Malaria. My 3rd year project allowed be to incorporate one of my other loves, music, into my studies by performing a literature review focus on whether musical training could improve perception and appreciation of music in cochlear implant wearers. In my master’s year I applied to work in the Ghafourian laboratory, due to my interest in neuroscience we developed a project whereby I created decision trees to determine whether the efficacy of antidepressants could be improved. This wide variety of projects in pharmaceutical chemistry, neuroscience and computational science, gave me a varied skill set which is a perfect fit for my PhD in the Waltho laboratory as I will be able to use all the skills I have acquired through these projects and apply them to a key area of interest for me, cell signalling in disease.

My project

Kinases are a large ubiquitous family of 518 Phosphotransfer enzymes which constitute 2% of the human genome.  They are therefore responsible for a vast number of diseases, in particular cancer, but they have also been associated with neurological, inflammatory diseases as well as developmental disorders. Although this is a well-studied family of proteins, targeting them with therapeutics is a challenge for two main reasons.

Firstly, the majority of kinase inhibitors are ATP competitive. This poses a problem as there is a large sequence similarity in the active site for most kinases, therefore, inhibitors lack selectivity causing off-target effects by inhibiting other kinases. This makes tolerability low in patients with them experiencing severe side effects.

Secondly, resistance mutations often occur in the ATP binding site rendering the inhibitors ineffective a key example of this is the T315I mutation in 30% of patients with chronic myelogenous leukaemia.

Therefore, one of the approaches being considered to tackle this major issue is using allosteric inhibitors which bind to sites outside of the active site and can be used either individually or in combination with ATP competitive inhibitors. These inhibitors have greater selectivity and are a region less susceptible to mutations. Allosteric inhibitors are generally discovered through serendipity or high throughput screening which are time-consuming processes, therefore, the aim of my project is to develop a novel method to identify allosteric inhibitor sites using 19F NMR. Depending on the success of the method with kinases the project may be expanded to include phosphatases and G-proteins to other major phosphatase transfer enzyme families.


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