Abstract
We recently reported the systematic ligand-based rational design and synthesis of monovalent Smac mimetics that bind preferentially to the BIR2 domain of the anti-apoptotic protein XIAP. Expanded structure-activity relationship (SAR) studies around these peptidomimetics led to compounds with significantly improved selectivity (>60-fold) for the BIR2 domain versus the BIR3 domain of XIAP. The potent and highly selective IAP antagonist 8q (ML183) sensitized TRAIL-resistant prostate cancer cells to apoptotic cell death, highlighting the merit of this probe compound as a valuable tool to investigate the biology of XIAP.
Copyright © 2013 Elsevier Ltd. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Binding Sites
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Biomimetic Materials / chemical synthesis*
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Biomimetic Materials / chemistry
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Biomimetic Materials / toxicity
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Cell Line, Tumor
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Cell Survival
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Drug Design*
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Drug Resistance, Neoplasm / drug effects
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Humans
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Molecular Docking Simulation
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Oligopeptides / chemical synthesis*
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Oligopeptides / chemistry
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Oligopeptides / toxicity
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Protein Binding
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Protein Structure, Tertiary
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Structure-Activity Relationship
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TNF-Related Apoptosis-Inducing Ligand / pharmacology
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X-Linked Inhibitor of Apoptosis Protein / antagonists & inhibitors*
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X-Linked Inhibitor of Apoptosis Protein / metabolism
Substances
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ML183 peptide
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Oligopeptides
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TNF-Related Apoptosis-Inducing Ligand
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X-Linked Inhibitor of Apoptosis Protein