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
  • 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.