To affinity and beyond: A systematic approach to the rapid elaboration of fragments into leads (REFiL)

Professor Martin Scanlon
Professor of Medicinal Chemistry, Director ARC Centre for Fragment-Based Design (CFBD)
Scientific Director Monash Fragment-Based Drug Design Platform
Monash Institute of Pharmaceutical Sciences, Monash University, presents: 

To affinity and beyond: A systematic approach to the rapid elaboration of fragments into leads (REFiL)

Fragment-based drug design (FBDD) has been widely adopted in both industry and academia and has proven to be a robust approach to identify small molecules that bind to a range of protein targets.1 Three compounds derived from programs of FBDD have now been approved for therapeutic use by the US Food and Drug Administration and many others are in advanced clinical trials. Biophysical binding assays are the mainstay for screening fragment libraries to identify suitable starting points for FBDD.

A significant challenge that is faced in almost all FBDD campaigns is to elaborate the initial fragment hits, which typically bind weakly to the target protein into a more potent lead molecule. To provide a more robust and systematic approach to this early phase of FBDD we have developed a workflow termed REFiL (Rapid Elaboration of Fragments into Leads). This workflow allows microscale parallel synthesis of targeted libraries that are designed to maximise chemical diversity in the products.

In this presentation I will describe the strategy that we have implemented combining biophysical binding assays centred largely around NMR spectroscopy, surface plasmon resonance (SPR) and X-ray crystallography with microscale parallel chemistry to enable a systematic and rapid approach whereby weakly-binding fragment hits can be elaborated into more potent ligands.

1. Erlanson, D. A.; Fesik, S. W.; Hubbard, R. E.; Jahnke, W.; Jhoti, H., Twenty years on: the impact of fragments on drug discovery. Nat Rev Drug Discov 2016, 15 (9), 605-19.