Abstract
The mammalian Target of Rapamycin (mTOR)-mediated signaling transduction pathway has been observed to be deregulated in a wide variety of cancer and metabolic diseases. Despite extensive clinical development efforts, the well-known allosteric mTOR inhibitor rapamycin and structurally related rapalogs have failed to show significant single-agent antitumor efficacy in most types of cancer. This limited clinical success may be due to the inability of the rapalogs to maintain a complete blockade mTOR-mediated signaling. Therefore, numerous efforts have been initiated to develop ATP-competitive mTOR inhibitors that would block both mTORC1 and mTORC2 complex activity. Here, we describe our experimental approaches to develop Torin1 using a medium throughput cell-based screening assay and structure-guided drug design.
MeSH terms
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Adenosine Triphosphate / metabolism*
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Animals
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Drug Design*
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HEK293 Cells
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High-Throughput Screening Assays / methods*
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Humans
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Mechanistic Target of Rapamycin Complex 1
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Mice
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Models, Molecular
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Molecular Structure
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Multiprotein Complexes
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Naphthyridines / chemistry*
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Naphthyridines / pharmacology
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Protein Kinase Inhibitors / chemistry*
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Protein Kinase Inhibitors / pharmacology
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Proteins / antagonists & inhibitors*
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Signal Transduction
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Sirolimus / pharmacology
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TOR Serine-Threonine Kinases
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Transcription Factors / antagonists & inhibitors*
Substances
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1-(4-(4-propionylpiperazin-1-yl)-3-(trifluoromethyl)phenyl)-9-(quinolin-3-yl)benzo(h)(1,6)naphthyridin-2(1H)-one
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CRTC2 protein, human
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Multiprotein Complexes
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Naphthyridines
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Protein Kinase Inhibitors
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Proteins
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Transcription Factors
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Adenosine Triphosphate
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Mechanistic Target of Rapamycin Complex 1
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TOR Serine-Threonine Kinases
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Sirolimus