Abstract
We report the systematic rational design and synthesis of new monovalent Smac mimetics that bind preferentially to the BIR2 domain of the anti-apoptotic protein XIAP. Characterization of compounds in vitro (including 9i; ML101) led to the determination of key structural requirements for BIR2 binding affinity. Compounds 9h and 9j sensitized TRAIL-resistant breast cancer cells to apoptotic cell death, highlighting the value of these probe compounds as tools to investigate the biology of XIAP.
Copyright © 2011 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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Apoptosis
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Apoptosis Regulatory Proteins / chemistry*
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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 / pharmacology
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Cell Line, Tumor
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Computer Simulation
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Drug Design
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Humans
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Intracellular Signaling Peptides and Proteins / chemistry
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Intracellular Signaling Peptides and Proteins / metabolism
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Mitochondrial Proteins / chemistry*
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Mitochondrial Proteins / metabolism
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Protein Binding
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Protein Structure, Tertiary
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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 / chemistry
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X-Linked Inhibitor of Apoptosis Protein / metabolism
Substances
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Apoptosis Regulatory Proteins
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DIABLO protein, human
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Intracellular Signaling Peptides and Proteins
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Mitochondrial Proteins
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TNF-Related Apoptosis-Inducing Ligand
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X-Linked Inhibitor of Apoptosis Protein