2017•Journal of Medicinal ChemistryOpen access
Discovery of a Potent Nonpeptidomimetic, Small-Molecule Antagonist of Cellular Inhibitor of Apoptosis Protein 1 (cIAP1) and X-Linked Inhibitor of Apoptosis Protein (XIAP)
Emiliano Tamanini, Ildiko M. Buck, Gianni Chessari, Elisabetta Chiarparin, James E. H. Day, Martyn Frederickson, Charlotte Griffiths-Jones, Keisha Hearn, Tom D. Heightman, Aman Iqbal, Christopher N. Johnson, Edward J. Lewis, Vanessa Martins, Torren M. Peakman, Michael Reader, Sharna J. Rich, George A. Ward, Pamela A. Williams, Nicola E. Wilsher
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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.