A deep structural understanding of ligand-protein binding is important for successful conduct of fragments-based drug design (FBDD) projects. X-ray crystallography plays a crucial role, but computational approaches also play and important part in optimizing key contacts between protein and ligand. Also important is an appreciation of the preferred solution conformation of the ligand. The integration of these three key areas is illustrated for the optimization of a series of dual cIAP1 and XIAP inhibitors. The Inhibitor of Apoptosis Proteins (IAPs) are key regulators of anti-apoptotic and pro-survival signalling pathways. Overexpression of IAPs occurs in various cancers and has been associated with tumour progression and resistance to treatment. Astex has successfully applied FBDD to develop a non-peptidic, potent dual cIAP1 and XIAP antagonist with a different pharmacological profile compared to previously reported, alanine-based, peptidomimetic antagonists. This presentation will describe the key steps of the fragment evolution to generate the lead series starting from fragment identification using our screening approach PyramidTM. X-ray crystallography enabled us to identify non-alanine fragments, which bind with mM affinity (LE &lt;&lt; 0.3) to both XIAP and cIAP1 which were optimised to a potent, dual XIAP and cIAP1 antagonist, which we have designated AT-IAP. The presentation highlights all the different aspects of the design process, from fragment to lead, that enabled us to quickly reach low nM level of potency (LE &gt; 0.3) and to generate an orally bioavailable antagonist which showed in vivo efficacy in a number of mouse tumour xenograft models.

Integration of x-ray crystallography, computational modelling and NMR conformational analysis data in fragment-based drug design

254th National Meeting (2017)

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