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Methods Mol Biol. 2012;821:447-60. doi: 10.1007/978-1-61779-430-8_29.

Development of ATP-competitive mTOR inhibitors.

Author information

1
Department of Cancer Biology, Dana Farber Cancer Institute, Boston, MA, USA.

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.

PMID:
22125084
PMCID:
PMC3964610
DOI:
10.1007/978-1-61779-430-8_29
[Indexed for MEDLINE]
Free PMC Article

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