Abstract
We have synthesized and evaluated a series of nonpeptidic, bivalent Smac mimetics as antagonists of the inhibitor of apoptosis proteins and new anticancer agents. All these bivalent Smac mimetics bind to full-length XIAP with low nanomolar affinities and function as ultrapotent antagonists of XIAP. While these Smac mimetics bind to cIAP1/2 with similar low nanomolar affinities, their potencies to induce degradation of cIAP1/2 proteins in cells differ by more than 100-fold. The most potent bivalent Smac mimetics inhibit cell growth with IC(50) from 1 to 3 nM in the MDA-MB-231 breast cancer cell line and are 100 times more potent than the least potent compounds. Determination of intracellular concentrations for several representative compounds showed that the linkers in these bivalent Smac mimetics significantly affect their intracellular concentrations and hence the overall cellular activity. Compound 27 completely inhibits tumor growth in the MDA-MB-231 xenografts while causing no signs of toxicity in the animals.
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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Animals
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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
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Apoptosis Regulatory Proteins
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Azocines / chemical synthesis*
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Azocines / chemistry
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Azocines / pharmacology
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Dipeptides / chemical synthesis*
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Dipeptides / chemistry
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Dipeptides / pharmacology
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Drug Screening Assays, Antitumor
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Humans
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Inhibitor of Apoptosis Proteins / metabolism*
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Intracellular Signaling Peptides and Proteins / chemistry*
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Mice
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Mitochondrial Proteins / chemistry*
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Molecular Mimicry
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Neoplasm Transplantation
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Protein Binding
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Stereoisomerism
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Structure-Activity Relationship
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Transplantation, Heterologous
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X-Linked Inhibitor of Apoptosis Protein / metabolism
Substances
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Antineoplastic Agents
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Apoptosis Regulatory Proteins
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Azocines
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DIABLO protein, human
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Dipeptides
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Inhibitor of Apoptosis Proteins
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Intracellular Signaling Peptides and Proteins
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Mitochondrial Proteins
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N,N'-((1,1'-(oxybis(pentane-5,1-diyl))bis(1H-1,2,3-triazole-4,1-diyl))bis(phenylmethylene))bis(6-(2-(methylamino)propanamido)-5-oxodecahydropyrrolo(1,2-a)azocine-3-carboxamide)
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X-Linked Inhibitor of Apoptosis Protein