Drugging challenging targets using fragment-based approaches.

Fragment-based approaches have now become firmly established in the drug discovery armoury. After notable early successes against protein kinases, the versatility and power of fragment-based approaches are increasingly being demonstrated on more diverse and difficult protein targets. This review highlights seven examples including targeting protein-protein interactions, a RNA polymerase and a DNA-binding protein. It shows how fragment-based approaches using small libraries have been successful when large HTS screens have failed. It also highlights the range of biophysical approaches being used and the interplay between experimental and in silico screens. The examples all show the iterative way in which potency is built up by synthetic elaboration of the initial fragment hits. Copyright 2010 Elsevier Ltd. All rights reserved.