Abstract
We report a second example of a general reaction screening approach to discover low molecular weight inhibitors of protein protein interactions. On the basis of the known pharmacophore model of SMAC mimetics, we predicted several inhibitors based on four different multicomponent reactions. The predicted inhibitors were subsequently synthesized, tested, and found to bind to the antiapoptotic protein X-linked inhibitor of apoptosis protein (XIAP) and showed cellular activity. Also the compounds are currently not highly potent. They could form a starting point for future medicinal chemistry optimization.
MeSH terms
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Amino Acid Motifs
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Amino Acid Sequence
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Antineoplastic Agents / chemical synthesis
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Antineoplastic Agents / chemistry*
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Antineoplastic Agents / pharmacology
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Cell Line, Tumor
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Cell Survival / drug effects
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Databases, Factual
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Drug Screening Assays, Antitumor
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Humans
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Models, Molecular*
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Peptidomimetics / chemical synthesis
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Peptidomimetics / chemistry*
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Peptidomimetics / pharmacology
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Piperazines / chemical synthesis
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Piperazines / chemistry
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Piperazines / pharmacology
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Protein Binding
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Stereoisomerism
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Structure-Activity Relationship
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Tetrazoles / chemical synthesis
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Tetrazoles / chemistry
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Tetrazoles / pharmacology
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Thiazoles / chemical synthesis
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Thiazoles / chemistry
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Thiazoles / pharmacology
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Thiazolidines / chemical synthesis
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Thiazolidines / chemistry
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Thiazolidines / 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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Antineoplastic Agents
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Peptidomimetics
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Piperazines
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Tetrazoles
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Thiazoles
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Thiazolidines
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X-Linked Inhibitor of Apoptosis Protein