Abstract
A series of compounds were designed and synthesized as antagonists of cIAP-1/2 and XIAP based upon our previously identified lead compound SM-122 (1). The most potent of these (7) binds to XIAP, cIAP-1, and cIAP-2 proteins with K(i) values of 36, <1, and <1.9 nM, respectively. Consistent with its potent binding affinities to IAPs, 7 effectively antagonizes XIAP in a cell-free caspase-9 functional assay, efficiently induces cIAP-1 degradation in cells at concentrations as low as 10 nM, and triggers activation of caspases and PARP cleavage in the MDA-MB-231 breast cancer cell line. Compound 7 potently inhibits cell growth in the MDA-MB-231 cancer cell line with an IC(50) value of 200 nM and is 9 times more potent than compound 1.
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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Alanine / analogs & derivatives*
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Alanine / chemical synthesis
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Alanine / chemistry
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Alanine / pharmacology
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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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Apoptosis / drug effects
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Baculoviral IAP Repeat-Containing 3 Protein
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Bridged Bicyclo Compounds, Heterocyclic / chemical synthesis*
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Bridged Bicyclo Compounds, Heterocyclic / chemistry
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Bridged Bicyclo Compounds, Heterocyclic / pharmacology
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Caspase 3 / metabolism
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Caspase Inhibitors
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Drug Screening Assays, Antitumor
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Humans
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Inhibitor of Apoptosis Proteins / antagonists & inhibitors*
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Inhibitor of Apoptosis Proteins / metabolism
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Molecular Structure
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Poly(ADP-ribose) Polymerases / metabolism
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Protein Binding
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Stereoisomerism
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Structure-Activity Relationship
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Ubiquitin-Protein Ligases
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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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6-(2-(methylamino)propanamido)-5-oxo-9-(2-phenylacetamido)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)decahydropyrrolo(1,2-a)azocine-3-carboxamide
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Antineoplastic Agents
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Bridged Bicyclo Compounds, Heterocyclic
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Caspase Inhibitors
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Inhibitor of Apoptosis Proteins
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X-Linked Inhibitor of Apoptosis Protein
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XIAP protein, human
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BIRC3 protein, human
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Baculoviral IAP Repeat-Containing 3 Protein
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Ubiquitin-Protein Ligases
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Poly(ADP-ribose) Polymerases
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Caspase 3
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Alanine