Fragment-Based Drug Discovery Targeting Inhibitor of Apoptosis Proteins: Discovery of a Non-Alanine Lead Series with Dual Activity Against cIAP1 and XIAP

J Med Chem. 2015 Aug 27;58(16):6574-88. doi: 10.1021/acs.jmedchem.5b00706.

Gianni Chessari ¹, Ildiko M Buck ¹, James E H Day ¹, Philip J Day ¹, Aman Iqbal ¹, Christopher N Johnson ¹, Edward J Lewis ¹, Vanessa Martins ¹, Darcey Miller ¹, Michael Reader ¹, David C Rees ¹, Sharna J Rich ¹, Emiliano Tamanini ¹, Marc Vitorino ¹, George A Ward ¹, Pamela A Williams ¹, Glyn Williams ¹, Nicola E Wilsher ¹, Alison J-A Woolford ¹

Affiliations

Affiliation

1 Astex Pharmaceuticals , 436 Cambridge Science Park, Milton Road, Cambridge, CB4 0QA, United Kingdom.

PMID: 26218264 DOI: 10.1021/acs.jmedchem.5b00706

Abstract

Inhibitor of Apoptosis proteins (IAPs) are important regulators of Apoptosis and pro-survival signaling pathways whose deregulation is often associated with tumor genesis and tumor growth. IAPs have been proposed as targets for Anticancer therapy, and a number of peptidomimetic IAP antagonists have entered clinical trials. Using our fragment-based screening approach, we identified nonpeptidic fragments binding with millimolar affinities to both cellular inhibitor of Apoptosis protein 1 (cIAP1) and X-linked inhibitor of Apoptosis protein (XIAP). Structure-based hit optimization together with an analysis of protein-ligand electrostatic potential complementarity allowed us to significantly increase binding affinity of the starting hits. Subsequent optimization gave a potent nonalanine IAP antagonist structurally distinct from all IAP antagonists previously reported. The lead compound had activity in cell-based assays and in a mouse xenograft efficacy model and represents a highly promising start point for further optimization.

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