Abstract
We have designed, synthesized, and evaluated a series of new compounds based upon our previously reported bivalent Smac mimetics. This led to the identification of compound 12 (SM-1200), which binds to XIAP, cIAP1, and cIAP2 with Ki values of 0.5, 3.7, and 5.4 nM, respectively, inhibits cell growth in the MDA-MB-231 breast cancer and SK-OV-3 ovarian cancer cell lines with IC50 values of 11.0 and 28.2 nM, respectively. Compound 12 has a much improved pharmacokinetic profile over our previously reported bivalent Smac mimetics and is highly effective in induction of rapid and durable tumor regression in the MDA-MB-231 xenograft model. These data indicate that compound 12 is a promising Smac mimetic and warrants extensive evaluation as a potential candidate for clinical development.
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 / pharmacokinetics
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Antineoplastic Agents / pharmacology
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Antineoplastic Agents / therapeutic use*
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Apoptosis Regulatory Proteins
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Area Under Curve
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Azocines / pharmacokinetics
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Azocines / pharmacology
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Azocines / therapeutic use*
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Blotting, Western
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Carrier Proteins / chemistry
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Carrier Proteins / pharmacology
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Caspase 3 / metabolism
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Caspase 9 / metabolism
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Cell Death / drug effects
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Dose-Response Relationship, Drug
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Humans
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Indicators and Reagents
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Inhibitor of Apoptosis Proteins / metabolism
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Male
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Mice
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Mice, Nude
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Mitochondrial Proteins / chemistry
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Mitochondrial Proteins / pharmacology
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Phenylenediamines / pharmacokinetics
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Phenylenediamines / pharmacology
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Phenylenediamines / therapeutic use*
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Rats
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Rats, Sprague-Dawley
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X-Linked Inhibitor of Apoptosis Protein / metabolism
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Xenograft Model Antitumor Assays
Substances
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Antineoplastic Agents
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Apoptosis Regulatory Proteins
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Azocines
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Carrier Proteins
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DIABLO protein, rat
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Indicators and Reagents
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Inhibitor of Apoptosis Proteins
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Mitochondrial Proteins
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N3,N3'-(-cyclohexane-1,4-diyl)bis(N8-benzhydryl-5-(2-(methylamino)propanamido)-6-oxooctahydropyrrolo(1,2-a)(1,5)diazocine-3,8(4H)-dicarboxamide)
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Phenylenediamines
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X-Linked Inhibitor of Apoptosis Protein
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Caspase 3
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Caspase 9