Discovery of a Potent Nonpeptidomimetic, Small-Molecule Antagonist of Cellular Inhibitor of Apoptosis Protein 1 (cIAP1) and X-Linked Inhibitor of Apoptosis Protein (XIAP)

  • J Med Chem. 2017 Jun 8;60(11):4611-4625. doi: 10.1021/acs.jmedchem.6b01877.
Emiliano Tamanini  1 ,  Ildiko M Buck  1 ,  Gianni Chessari  1 ,  Elisabetta Chiarparin  1 ,  James E H Day  1 ,  Martyn Frederickson  1 ,  Charlotte M Griffiths-Jones  1 ,  Keisha Hearn  1 ,  Tom D Heightman  1 ,  Aman Iqbal  1 ,  Christopher N Johnson  1 ,  Edward J Lewis  1 ,  Vanessa Martins  1 ,  Torren Peakman  1 ,  Michael Reader  1 ,  Sharna J Rich  1 ,  George A Ward  1 ,  Pamela A Williams  1 ,  Nicola E Wilsher  1
Affiliations
  • 1. Astex Pharmaceuticals , 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, U.K.
PMID: 28492317 DOI: 10.1021/acs.jmedchem.6b01877
Abstract

XIAP and cIAP1 are members of the inhibitor of Apoptosis protein (IAP) family and are key regulators of anti-apoptotic and pro-survival signaling pathways. Overexpression of IAPs occurs in various cancers and has been associated with tumor progression and resistance to treatment. Structure-based drug design (SBDD) guided by structural information from X-ray crystallography, computational studies, and NMR solution conformational analysis was successfully applied to a fragment-derived lead resulting in AT-IAP, a potent, orally bioavailable, dual antagonist of XIAP and cIAP1 and a structurally novel chemical probe for IAP biology.

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