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.
MeSH terms
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Animals
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Cell Line, Tumor
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Crystallography, X-Ray
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Drug Discovery
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HEK293 Cells
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Heterocyclic Compounds, 2-Ring / chemistry*
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Heterocyclic Compounds, 2-Ring / pharmacology*
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Humans
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Inhibitor of Apoptosis Proteins / antagonists & inhibitors*
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Mice
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Mice, Inbred BALB C
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Mice, SCID
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Peptidomimetics
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Piperazines / chemistry*
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Piperazines / pharmacology*
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Small Molecule Libraries
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Structure-Activity Relationship
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X-Linked Inhibitor of Apoptosis Protein / antagonists & inhibitors*
Substances
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AT-IAP compound
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Heterocyclic Compounds, 2-Ring
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Inhibitor of Apoptosis Proteins
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Peptidomimetics
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Piperazines
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Small Molecule Libraries
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X-Linked Inhibitor of Apoptosis Protein
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XIAP protein, human