Abstract
Affinity selection screening of macrocycle libraries derived from DNA-programmed chemistry identified XIAP BIR2 and BIR3 domain inhibitors that displace bound pro-apoptotic caspases. X-ray cocrystal structures of key compounds with XIAP BIR2 suggested potency-enhancing structural modifications. Optimization of dimeric macrocycles with similar affinity for both domains were potent pro-apoptotic agents in cancer cell lines and efficacious in shrinking tumors in a mouse xenograft model.
MeSH terms
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Animals
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Antineoplastic Agents / chemistry*
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Antineoplastic Agents / pharmacokinetics
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Antineoplastic Agents / therapeutic use*
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Breast / drug effects
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Breast / metabolism
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Breast / pathology
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Breast Neoplasms / drug therapy*
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Breast Neoplasms / metabolism
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Breast Neoplasms / pathology
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Caspase 3 / metabolism
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Cell Line, Tumor
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Crystallography, X-Ray
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Drug Discovery
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Female
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Gene Library
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Humans
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Macrocyclic Compounds / chemistry*
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Macrocyclic Compounds / pharmacokinetics
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Macrocyclic Compounds / therapeutic use*
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Mice
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Models, Molecular
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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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Antineoplastic Agents
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Macrocyclic Compounds
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X-Linked Inhibitor of Apoptosis Protein
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Caspase 3