A systematic approach to fragment elaboration will enable rapid prosecution of novel target classes and identify valuable lead molecules for development

One major challenge in FBD is that the small fragments identified in biophysical screens usually bind to their targets with low affinity. Consequently, efficient and sensitive methods are required to select the most suitable fragments for development into potent and selective tool compounds or drug candidates.

We have developed a strategy, termed REFiL (Rapid Elaboration of Fragments into Leads), to address this problem. REFiL provides a coordinated approach to elaborating fragments into more potent hit compounds through the following steps:

  1. Identify positions on a fragment hit amenable to chemical modification to improve binding affinity. This is determined through structural information of the target and fragment, or through SAR derived from commercially available analogues.
  2. Perform systematic process of chemical modification at each selected vector using microscale parallel chemical synthesis, exploring a diverse range of chemical structures around a hit fragment.
  3. Screen microscale elaborated fragments using off-rate screening (ORS) by surface plasmon resonance (SPR).

In collaboration with our industry partner, we will optimise the REFiL strategy. The outcome of this work will be a medicinal chemistry tool-kit that is optimised for fragment elaboration. This will accelerate the process of target validation, development of intellectual property around novel chemical entities and aid in research translation.

On-going projects:

  • Novel chemoinformatic methods for fragment exploration and design
  • Microscale parallel synthesis and biophysical screening for rapid fragment development
  • Developing isoform-selective inhibitors of fatty acid-binding proteins as novel therapeutics for metabolic disorders and cancer
  • Development of inhibitors for the extra-terminal domain of bromodomain-3 (BRD3-ET) using a REFiL approach
  • Finding inhibitors of novel antivirulence targets