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

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

Affiliation

  • 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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