Selective inhibitors of mTORC1 activate 4EBP1 and suppress tumor growth Journal Article

Authors: Lee, B. J.; Boyer, J. A.; Burnett, G. L.; Thottumkara, A. P.; Tibrewal, N.; Wilson, S. L.; Hsieh, T.; Marquez, A.; Lorenzana, E. G.; Evans, J. W.; Hulea, L.; Kiss, G.; Liu, H.; Lee, D.; Larsson, O.; McLaughlan, S.; Topisirovic, I.; Wang, Z.; Wang, Z.; Zhao, Y.; Wildes, D.; Aggen, J. B.; Singh, M.; Gill, A. L.; Smith, J. A. M.; Rosen, N.
Article Title: Selective inhibitors of mTORC1 activate 4EBP1 and suppress tumor growth
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.]. © 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.
Journal Title: Nature Chemical Biology
Volume: 17
Issue: 10
ISSN: 1552-4450
Publisher: Nature Publishing Group  
Date Published: 2021-10-01
Start Page: 1065
End Page: 1074
Language: English
DOI: 10.1038/s41589-021-00813-7
PUBMED: 34168367
PROVIDER: scopus
PMCID: PMC9249104
Notes: Article -- Source: Scopus There are two Erratum published for this article: doi: 10.1038/s41589-021-00843-1 - Corrects funding acknowledgements; doi: 10.1038/s41589-021-00905-4 - Corrects figure labeling errors and typos
Citation Impact
MSK Authors
  1. Neal Rosen
    417 Rosen
  2. Jacob Andrew Boyer
    7 Boyer