Development of boron-based dynamic covalent enzyme inhibitors

Enzyme inhibition is a key priority area in drug development. Of the various strategies available, covalent inhibitors offer a unique platform for drug development; however, the inherent risk of off-target effects from the use of reactive and irreversible inhibitors can be problematic for development. Dynamic covalent inhibitors offer a solution to this issue. In particular, the dynamic equilibrium between boronic acid and the cognate boronates, provides a foundation for next generation dynamic covalent inhibitors. Indeed, this has been exemplified in the developmet of blockbuster antibiotics, such as taniborbactam, that function as serine protease inhibitors. This project seeks to develop novel boron-based dynamic covalent inhibitors of a target enzyme (Autotaxin) that is implicated in several disease states, including cancer and fibrosis, amongst others.