Fully-functionalised probes for chemical proteomics

Identifying and exploring new biologically-relevant chemical space is a major challenge that is central to both chemical biology and medicinal chemistry. Readily-available chemical probes can dramatically influence the biomedical science that is investigated experimentally. Yet, identifying new biologically-relevant chemical space is hampered by the uneven exploration of both biology and chemistry. Biologists favourite proteins are largely unchanged for more than 20 years despite a lack of evidence supporting their particular relevance to disease. Moreover, bioactive small molecule discovery continues to be underpinned by a remarkably narrow reaction toolkit that limits the scaffold diversity of explored chemical space. How, then, can new connections between phenotypes, target proteins and bioactive chemotypes be established to further our understanding of biology and, ultimately, to treat disease?
This project will focus on the development of approaches that enable the one-pot synthesis of diverse small molecule probes that are already fully-functionalised for chemical biology studies. The resulting probes will thus reside in novel chemical space; will be armed with diverse electrophilic warheads; and will already be functionalised with clickable alkyne tags. The student will demonstrate that these diverse chemical probes can be harnessed to unlock new regions of biologically-relevant chemical space, and may reveal insights into the molecular basis of cell biology mechanisms. These tools may unlock new therapeutic strategies for the treatment of disease.
The specific objectives are:
1. To identify viable substrate sets for one-pot chemical probe synthesis;
2. To prepare a diverse set of fully-functionalised probes using one-pot connective chemistry
3. To assess the probe set in model biological systems