Abstract
We report here the synthesis and structure-activity relationship (SAR) of a novel series of mammalian target of rapamycin (mTOR) kinase inhibitors. A series of 4,6- or 1,7-disubstituted-3,4-dihydropyrazino[2,3-b]pyrazine-2(1H)-ones were optimized for in vivo efficacy. These efforts resulted in the identification of compounds with excellent mTOR kinase inhibitory potency, with exquisite kinase selectivity over the related lipid kinase PI3K. The improved PK properties of this series allowed for exploration of in vivo efficacy and ultimately the selection of CC-223 for clinical development.
MeSH terms
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Animals
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Antineoplastic Agents / chemical synthesis
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Antineoplastic Agents / pharmacology*
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Drug Discovery*
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Humans
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Male
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Models, Molecular
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Molecular Structure
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Phosphoinositide-3 Kinase Inhibitors*
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Prostatic Neoplasms / drug therapy*
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Protein Kinase Inhibitors / chemical synthesis
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Protein Kinase Inhibitors / pharmacology*
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Pyrazines / chemical synthesis
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Pyrazines / pharmacology*
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Rats
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Signal Transduction / drug effects*
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Structure-Activity Relationship
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TOR Serine-Threonine Kinases / antagonists & inhibitors*
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Tumor Cells, Cultured
Substances
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Antineoplastic Agents
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CC-223
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Phosphoinositide-3 Kinase Inhibitors
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Protein Kinase Inhibitors
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Pyrazines
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TOR Serine-Threonine Kinases