Selective inhibitors of mTORC1 activate 4EBP1 and suppress tumor growth

Bianca J. Lee, Jacob A. Boyer, G. Leslie Burnett, Arun P. Thottumkara, Nidhi Tibrewal, Stacy L. Wilson, Tientien Hsieh, Abby Marquez, Edward G. Lorenzana, James W. Evans, Laura Hulea, Gert Kiss, Hui Liu, Dong Lee, Ola Larsson, Shannon McLaughlan, Ivan Topisirovic, Zhengping Wang, Zhican Wang, Yongyuan ZhaoDavid Wildes, James B. Aggen, Mallika Singh, Adrian L. Gill, Jacqueline A.M. Smith, Neal Rosen

Research output: Contribution to journalArticlepeer-review

28 Scopus citations

Abstract

The clinical benefits of pan-mTOR active-site inhibitors are limited by toxicity and relief of feedback inhibition of receptor expression. To address these limitations, we designed a series of compounds that selectively inhibit mTORC1 and not mTORC2. These ‘bi-steric inhibitors’ comprise a rapamycin-like core moiety covalently linked to an mTOR active-site inhibitor. Structural modification of these components modulated their affinities for their binding sites on mTOR and the selectivity of the bi-steric compound. mTORC1-selective compounds potently inhibited 4EBP1 phosphorylation and caused regressions of breast cancer xenografts. Inhibition of 4EBP1 phosphorylation was sufficient to block cancer cell growth and was necessary for maximal antitumor activity. At mTORC1-selective doses, these compounds do not alter glucose tolerance, nor do they relieve AKT-dependent feedback inhibition of HER3. Thus, in preclinical models, selective inhibitors of mTORC1 potently inhibit tumor growth while causing less toxicity and receptor reactivation as compared to pan-mTOR inhibitors. [Figure not available: see fulltext.].

Original languageEnglish (US)
Pages (from-to)1065-1074
Number of pages10
JournalNature Chemical Biology
Volume17
Issue number10
DOIs
StatePublished - Oct 2021
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

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