2. Academic Validation
  3. Selective inhibitors of mTORC1 activate 4EBP1 and suppress tumor growth

Selective inhibitors of mTORC1 activate 4EBP1 and suppress tumor growth

  • Nat Chem Biol. 2021 Oct;17(10):1065-1074. doi: 10.1038/s41589-021-00813-7.
Bianca J Lee  # 1,  Jacob A Boyer  # 2 3,  G Leslie Burnett 4,  Arun P Thottumkara 4,  Nidhi Tibrewal 5,  Stacy L Wilson 1,  Tientien Hsieh 5,  Abby Marquez 5,  Edward G Lorenzana 1,  James W Evans 1,  Laura Hulea 6 7 8,  Gert Kiss 5,  Hui Liu 9,  Dong Lee 10,  Ola Larsson 9,  Shannon McLaughlan 6,  Ivan Topisirovic 6,  Zhengping Wang 10,  Zhican Wang 10,  Yongyuan Zhao 10,  David Wildes 1,  James B Aggen 4,  Mallika Singh 1,  Adrian L Gill 4,  Jacqueline A M Smith 11,  Neal Rosen 12
Affiliations

Affiliations

  • 1 Department of Biology, Revolution Medicines, Inc., Redwood City, CA, USA.
  • 2 Louis V. Gerstner Jr. Graduate School of Biomedical Sciences, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
  • 3 Program in Molecular Pharmacology, Department of Medicine, Memorial Sloan-Kettering Cancer Center (MSKCC), New York, NY, USA.
  • 4 Department of Chemistry, Revolution Medicines, Inc., Redwood City, CA, USA.
  • 5 Department of Discovery Technologies, Revolution Medicines, Inc., Redwood City, CA, USA.
  • 6 Gerald Bronfman Department of Oncology and Departments of Biochemistry and Experimental Medicine, Lady Davis Institute, McGill University, Montréal, QC, Canada.
  • 7 Département de Médecine, Département de Biochimie et Médecine Moléculaire, Université de Montréal, Montréal, QC, Canada.
  • 8 Maisonneuve-Rosemont Hospital Research Centre, Montréal, QC, Canada.
  • 9 Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institute, Solna, Sweden.
  • 10 Department of Non-clinical Development and Clinical Pharmacology, Revolution Medicines, Inc., Redwood City, CA, USA.
  • 11 Department of Biology, Revolution Medicines, Inc., Redwood City, CA, USA. jan@revmed.com.
  • 12 Program in Molecular Pharmacology, Department of Medicine, Memorial Sloan-Kettering Cancer Center (MSKCC), New York, NY, USA. rosenn@mskcc.org.
  • # Contributed equally.
PMID: 34168367 DOI: 10.1038/s41589-021-00813-7
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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-143510
    99.20%, mTORC1 Inhibitor