A Systems Chemical Biology Paradigm to Accelerate the Discovery of New Medicines for Patients: A Prosperity Partnership for a Healthier Nation

Lead Research Organisation: The Francis Crick Institute
Department Name: Research


Discovery and development of new medicines for patients is a long and complex process with an inherently low probability of success. Fortunately, rapid advances in technologies to read, interpret, and precisely manipulate the 'genetic code' are transforming our understanding of how small genetic variations can affect the onset of human disease.
Subtle deviations in genetic sequence may lead to alteration in 'proteins' (basic building blocks of human cells) which, in turn, can influence the behaviour of specific cell types and eventually result in establishment of disease. Most medicines are therefore targeted towards a specific protein - normally to suppress, or enhance, the function of this protein. With many potential genes being associated with disease, the challenge of working through all these possible associations is daunting: there are a great many factors to evaluate. In most drug discovery campaigns, an early goal will be to identify chemical 'probes' (prototype drug molecules) that can precisely interfere with a given target to understand its therapeutic potential. Typically, this is a slow process which has several stages: firstly, producing small amounts of isolated protein; next, screening large 'libraries' of compounds (often more than 1,000,000); then following up the most promising compounds with experiments in human cells to study the target in question. This process can take many months to
complete and must be repeated for each target of interest.
The purpose of this Prosperity Partnership is to develop and industrialise emerging technology in Chemical Biology employing 'reactive fragment screening'. The exciting potential of this approach is its ability to simultaneously identify new, disease-relevant, protein targets and the chemical probes needed to study them in live cells. This has the advantage of bypassing the need for protein production and opens the possibility of studying many proteins in parallel rather than one at a time.
'Fragments' are stripped down versions of drug molecules which are much less complex than their fully elaborated counterparts. Consequently, the number of fragments required to populate a library is much smaller than a traditional screening library (100-1,000 molecules versus 1,000,000 or more) which typically accelerates the process of screening compounds. Although fragments do not bind strongly to their protein targets, by introducing a reactive molecular 'feature' on to each library compound it is possible to permanently capture the full range of targets bound by each fragment.
Subsequently, mass-spectrometry based 'chemoproteomics' (a sensitive analytical technique) can be used to build a map of the proteins which are captured by each fragment molecule in a disease-relevant cellular context. By adopting advanced computational techniques, it will be possible to link together outcomes of experiments involving 'genetic manipulation' with chemistry-directed experiments involving 'protein manipulation' to observe how each of these treatments changes the behaviour of a cell in a disease setting.
Although more technically demanding, this advanced technology will enable protein targets to be advanced into full drug discovery at a faster pace and with higher levels of confidence than previously possible. Given the inherent difficulties of discovering and developing new medicines, and the high failure rates, new technologies which can reduce bottlenecks in discovery will enable more cost-effective development of new medicines and will ultimately benefit society as a whole.
The Prosperity Partnership will dramatically expand the fruitful collaborative relationship between GSK and the Francis Crick Institute, established 5 years ago, which has already led to chemical probe-driven research breakthroughs. To achieve the goals of this ambitious Partnership, GSK and Crick scientists will work side-by-side at our Stevenage and London research centres.
Description Chemoproteomic screening of DUBs 
Organisation GlaxoSmithKline (GSK)
Department GlaxoSmithKline, Stevenage
Country United Kingdom 
Sector Private 
PI Contribution Recombinant protein production, enzymatic assays Structural studies, progression of initial fragment hits into selective chemical probes
Collaborator Contribution Synthesis of covalent fragment library; Chemoproteomic screening of library; Follow up mass spectrometric analysis
Impact Publication describing the work has been submitted to bioRxiv
Start Year 2021