Recently, fragment-based methods have successfully delivered clinical candidates for targets considered untractable using traditional methods.At Astex, fragment based discovery is driven by a combination of high-throughput crystallographic screening and biophysical methods. This methodology is binding site agnostic, allowing the identification of ligands at potential allosteric as well as orthosteric sites. In addition, the detailed structural insights provided by crystallographic screening and structure-guided optimization allow parsimonious building of affinity, which provides drug candidates with enhanced ligand efficiency likely to minimize attrition in development.The talk will describe the application of fragment based methods to the discovery of (i) a novel chemotype disrupting protein-protein interactions in the Inhibitor of Apoptosis Protein (IAP) family with potent in vivo anti-tumor activity, and (ii) potent antiviral allosteric inhibitors of the full length hepatitis-C virus NS3/4a enzyme, which stabilize the interaction between the protease and helicase domains, leading to an auto-inhibited conformation of the holoprotein.

Fragment targeting of protein-protein interactions and allosteric modulation

245th National Meeting (2013)

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