Development of ATP-competitive mTOR inhibitors

Qingsong Liu, Seong A. Kang, Carson C. Thoreen, Wooyoung Hur, Jinhua Wang, Jae Won Chang, Andrew Markhard, Jianming Zhang, Taebo Sim, David M. Sabatini, Nathanael S. Gray

Research output: Chapter in Book/Report/Conference proceedingChapter

20 Citations (Scopus)

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.

Original languageEnglish
Title of host publicationmTOR
Subtitle of host publicationMethods and Protocols
EditorsThomas Weichhart
Pages447-460
Number of pages14
DOIs
Publication statusPublished - 2012

Publication series

NameMethods in Molecular Biology
Volume821
ISSN (Print)1064-3745

Keywords

  • Akt
  • PI3K
  • PIKK
  • Rapamycin
  • Torin1
  • mTOR
  • mTORC1
  • mTORC2

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics

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  • Cite this

    Liu, Q., Kang, S. A., Thoreen, C. C., Hur, W., Wang, J., Chang, J. W., Markhard, A., Zhang, J., Sim, T., Sabatini, D. M., & Gray, N. S. (2012). Development of ATP-competitive mTOR inhibitors. In T. Weichhart (Ed.), mTOR: Methods and Protocols (pp. 447-460). (Methods in Molecular Biology; Vol. 821). https://doi.org/10.1007/978-1-61779-430-8_29