ProfessorDavid Mann

CURRENT RESEARCH
Our lab is focused on using modern chemical biological techniques to probe biological function. To this end, we have developed a novel screening platform (quantitative irreversible tethering, qIT) to identify chemical fragments that specifically and covalently bind to a given protein. This method allows us to rapidly identify compounds that can act as starting points for the development of selective biological probes and potential therapeutics for a given target protein.

Figure 1: Overview of quantitative irreversible tethering.

We have extensively validated the qIT methodology using the cell cycle regulatory kinase cyclin-dependent kinase 2 (cdk2) demonstrating hit identification and subsequent use of covalent determining structure/activity relationships to improve hit selectivity. We are currently pursuing a range of targets in the oncology space using qIT.
Figure 2: Development of covalent structure/activity relationships (covSAR) developed against a cdk2 model.


In addition, we have a long-standing interest in the determination of the substrates of protein kinases. These enzymes are key regulators of almost all eukaryotic processes but substrate identification is difficult: there are over 500 kinases encoded by the human genome, each performing the same biological transformation on a range of overlapping protein substrates. We are currently exploring the incorporation of non-natural amino acids into protein kinases to enable crosslinking of kinase and substrate with subsequent substrate purification and proteomic identification.