Poster Presentation The 48th Lorne Conference on Protein Structure and Function 2023

Rapid Elaboration of Fragments into Leads (REFiL) (#434)

Luke A Adams 1 2 3 , Lorna E Wilkinson-White 4 , Menachem J Gunzburg 3 5 , Biswaranjan Mohanty 4 , Matthew R Bentley 5 , Olga V Ilyichova 5 , Martin J Scanlon 2 3 5 , Ben Capuano 2 5 , Joel P Mackay 2 6 , Bradley C Doak 3 5
  1. Monash Institute of Pharmaceutical Sciences, ARC Centre for Fragment-Based Design, Melbourne, Victoria
  2. ARC Centre for Fragment-Based Design, Monash Institute of Pharmaceutical Sciences, Melbourne, Victoria, Australia
  3. Monash Fragment Platform, Monash Institute of Pharmaceutical Sciences, Melbourne, Victoria, Australia
  4. Sydney Analytical Core Research Facility, University of Sydney, Sydney, NSW, Australia
  5. Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Melbourne, Victoria 3052, Australia
  6. School of Life and Environmental Sciences, University of Sydney, Sydney, New South Wales, Australia

One of the major challenges in fragment-based drug design is developing weak binding fragment hits into lead-like compounds that can be used as biological tools or precursors for a drug discovery campaign. To address this issue, we have developed a systematic workflow that enables the Rapid Elaboration of Fragments into Leads (REFiL).1,2   

REFiL provides an integrated workflow to identify, prioritise and then elaborate fragment hits. The first stage involves screening of commercial analogues to rank hits and establish vectors that are amenable to modification. These vectors are explored by microscale parallel synthesis of diverse libraries, using chemoinformatically designed reagent sets. Products are initially evaluated using biophysical assays including X-ray crystallography and SPR.2,3 Using this approach we have been able to significantly improve the binding affinity of fragment hits in just a few rounds of synthesis.

The work presented will demonstrate the REFiL workflow and how this strategy could be applied to a number of proteins for an efficient method of fragment evolution to drug leads.

  1. 1. L. A. Adams, L. E. Wilkinson-White, M. J. Gunzburg, S. J. Headey, M. J. Scanlon, B. Capuano, J. P. Mackay and B. C. Doak, “Rapid Elaboration of Fragments into Leads Applied to Bromodomain-3 Extra Terminal Domain” ChemRxiv 2020. This content is a preprint and has not been peer-reviewed.
  2. 2. M. R. Bentley, O. V. Ilyichova, G. Wang, M. L. Williams, G. Sharma, W. S. Alwan, R. L. Whitehouse, B. Mohanty, P. J. Scammells, B. Heras, J. L. Martin, M. Totsika, B. Capuano, B. C. Doak and M. J. Scanlon, “Rapid Elaboration of Fragments into Leads by X‑ray Crystallographic Screening of Parallel Chemical Libraries (REFiLX)” J. Med. Chem. 2020, 63, 6863-6875.
  3. 3. J. B. Murray, S. D. Roughley, N. Matassova, P. A. Brough “Off-Rate Screening (ORS) by Surface Plasmon Resonance. An Efficient Method to Kinetically Sample Hit to Lead Chemical Space from Unpurified Reaction Products” J. Med. Chem. 2014, 57, 2845-2850.