CoChat
Sign Up
Cited by 88

The DOI matches its Crossref record; 10 of the 10 references it cites were found in a registry or an index.

A small molecule inhibitor of Rheb selectively targets mTORC1 signaling

Mahoney, Sarah J., Narayan, Sridhar, Molz, Lisa, Berstler, Lauren A., Kang, Seong A., Vlasuk, George P., Saiah, Eddine·2018·Nature Communications
DOI 10.1038/s41467-018-03035-zPMC PMC5803267
Open this paper in CoChat — free account

Abstract

The small G-protein Rheb activates the mechanistic target of rapamycin complex 1 (mTORC1) in response to growth factor signals. mTORC1 is a master regulator of cellular growth and metabolism; aberrant mTORC1 signaling is associated with fibrotic, metabolic, and neurodegenerative diseases, cancers, and rare disorders. Point mutations in the Rheb switch II domain impair its ability to activate mTORC1. Here, we report the discovery of a small molecule (NR1) that binds Rheb in the switch II domain and selectively blocks mTORC1 signaling. NR1 potently inhibits mTORC1 driven phosphorylation of ribosomal protein S6 kinase beta-1 (S6K1) but does not inhibit phosphorylation of AKT or ERK. In contrast to rapamycin, NR1 does not cause inhibition of mTORC2 upon prolonged treatment. Furthermore, NR1 potently and selectively inhibits mTORC1 in mouse kidney and muscle in vivo. The data presented herein suggest that pharmacological inhibition of Rheb is an effective approach for selective inhibition of mTORC1 with therapeutic potential.

Overview

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1038/s41467-018-03035-z

Cites

10 of 10 references verified0 citation errors · 0 not checkable

Statistics

Verification

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Citations

Cites

Flagged first, then by citations

Show all 10 references

Research works printed but not linked: 60

  1. Laplante, M. & Sabatini, D. M. mTOR signaling in growth control and disease. Cell 149, 274–293 (2012). · DOI · Paper page
  2. Dibble, C. C. & Manning, B. D. Signal integration by mTORC1 coordinates nutrient input with biosynthetic output. Nat. Cell Biol. 15, 555–564 (2013). · DOI
  3. Oh, W. J. & Jacinto, E. mTOR complex 2 signaling and functions. Cell Cycle 10, 2305–2316 (2011). · DOI
  4. Gui, Y. S. et al. mTOR overactivation and compromised autophagy in the pathogenesis of pulmonary fibrosis. PLoS ONE 10, e0138625 (2015). · DOI
  5. Crino, P. B. The mTOR signalling cascade: paving new roads to cure neurological disease. Nat. Rev. Neurol. 12, 379–392 (2016). · DOI · Paper page
  6. Jahrling, J. B. & Laberge, R. M. Age-related neurodegeneration prevention through mTOR inhibition: potential mechanisms and remaining questions. Curr. Top. Med. Chem. 15, 2139–2151 (2015). · DOI
  7. Fernandez, D. & Perl, A. mTOR signaling: a central pathway to pathogenesis in systemic lupus erythematosus? Discov. Med. 9, 173–178 (2010).
  8. Populo, H., Lopes, J. M. & Soares, P. The mTOR signalling pathway in human cancer. Int. J. Mol. Sci. 13, 1886–1918 (2012). · DOI · Paper page
  9. Sampson, J. R. Therapeutic targeting of mTOR in tuberous sclerosis. Biochem. Soc. Trans. 37, 259–264 (2009). · DOI
  10. Li, J., Kim, S. G. & Blenis, J. Rapamycin: one drug, many effects. Cell Metab. 19, 373–379 (2014). · DOI · Paper page
  11. Kaplan, B., Qazi, Y. & Wellen, J. R. Strategies for the management of adverse events associated with mTOR inhibitors. Transplant. Rev. 28, 126–133 (2014). · DOI
  12. Sarbassov, D. D. et al. Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Mol. Cell 22, 159–168 (2006). · DOI · Paper page
  13. Lamming, D. W. et al. Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity. Science 335, 1638–1643 (2012). · DOI · Paper page
  14. Basu, B. et al. First-in-human pharmacokinetic and pharmacodynamic study of the dual m-TORC 1/2 inhibitor AZD2014. Clin. Cancer Res. 21, 3412–3419 (2015). · DOI
  15. Mateo, J. et al. A first in man, dose-finding study of the mTORC1/mTORC2 inhibitor OSI-027 in patients with advanced solid malignancies. Br. J. Cancer 114, 889–896 (2016). · DOI
  16. Asahina, H. et al. Safety and tolerability of AZD8055 in Japanese patients with advanced solid tumors; a dose-finding phase I study. Invest. New Drugs 31, 677–684 (2013). · DOI
  17. Naing, A. et al. Safety, tolerability, pharmacokinetics and pharmacodynamics of AZD8055 in advanced solid tumours and lymphoma. Br. J. Cancer 107, 1093–1099 (2012). · DOI
  18. Heard, J. J., Fong, V., Bathaie, S. Z. & Tamanoi, F. Recent progress in the study of the Rheb family GTPases. Cell. Signal. 26, 1950–1957 (2014). · DOI
  19. Yu, Y. et al. Structural basis for the unique biological function of small GTPase RHEB. J. Biol. Chem. 280, 17093–17100 (2005). · DOI
  20. Long, X., Lin, Y., Ortiz-Vega, S., Busch, S. & Avruch, J. The Rheb switch 2 segment is critical for signaling to target of rapamycin complex 1. J. Biol. Chem. 282, 18542–18551 (2007). · DOI
  21. Basso, A. D. et al. The farnesyl transferase inhibitor (FTI) SCH66336 (lonafarnib) inhibits Rheb farnesylation and mTOR signaling. Role in FTI enhancement of taxane and tamoxifen anti-tumor activity. J. Biol. Chem. 280, 31101–31108 (2005). · DOI
  22. Ding, H. et al. Farnesyltransferase inhibitor tipifarnib inhibits Rheb prenylation and stabilizes Bax in acute myelogenous leukemia cells. Haematologica 99, 60–69 (2014). · DOI
  23. Baines, A. T., Xu, D. & Der, C. J. Inhibition of Ras for cancer treatment: the search continues. Future Med. Chem. 3, 1787–1808 (2011). · DOI
  24. Wang, J., Yao, X. & Huang, J. New tricks for human farnesyltransferase inhibitor: cancer and beyond. Med. Chem. Commun. 8, 841–854 (2017). · DOI
  25. Wennerberg, K., Rossman, K. L. & Der, C. J. The Ras superfamily at a glance. J. Cell Sci. 118, 843–846 (2005). · DOI
  26. Spiegel, J., Cromm, P. M., Zimmermann, G., Grossmann, T. N. & Waldmann, H. Small-molecule modulation of Ras signaling. Nat. Chem. Biol. 10, 613–622 (2014). · DOI
  27. Shang, X. et al. Rational design of small molecule inhibitors targeting RhoA subfamily Rho GTPases. Chem. Biol. 19, 699–710 (2012). · DOI
  28. Gao, J. et al. Automated NMR fragment based screening identified a novel interface blocker to the LARG/RhoA complex. PLoS ONE 9, e88098 (2014). · DOI
  29. Erlanson, D. A., Jahnke, W., Mannhold, R., Kubinyi, H. & Folkers G. Fragment-Based Drug Discovery: Lessons and Outlook Vol. 67 (Wiley, Weinheim, Germany, 2016). · DOI
  30. Meyer, B. & Peters, T. NMR spectroscopy techniques for screening and identifying ligand binding to protein receptors. Angew. Chem. Int. Ed. 42, 864–890 (2003). · DOI
  31. Karassek, S. et al. Ras homolog enriched in brain (Rheb) enhances apoptotic signaling. J. Biol. Chem. 285, 33979–33991 (2010). · DOI
  32. Maurer, T. et al. Small-molecule ligands bind to a distinct pocket in Ras and inhibit SOS-mediated nucleotide exchange activity. Proc. Natl Acad. Sci. USA 109, 5299–5304 (2012). · DOI · Paper page
  33. Annis, D. A., Nickbarg, E., Yang, X., Ziebell, M. R. & Whitehurst, C. E. Affinity selection-mass spectrometry screening techniques for small molecule drug discovery. Curr. Opin. Chem. Biol. 11, 518–526 (2007). · DOI
  34. Tabancay, A. P. Jr. et al. Identification of dominant negative mutants of Rheb GTPase and their use to implicate the involvement of human Rheb in the activation of p70S6K. J. Biol. Chem. 278, 39921–39930 (2003). · DOI
  35. Anastassiadis, T., Deacon, S. W., Devarajan, K., Ma, H. & Peterson, J. R. Comprehensive assay of kinase catalytic activity reveals features of kinase inhibitor selectivity. Nat. Biotechnol. 29, 1039–1045 (2011). · DOI · Paper page
  36. Kang, S. A. et al. mTORC1 phosphorylation sites encode their sensitivity to starvation and rapamycin. Science 341, 1236566 (2013). · DOI
  37. Choo, A. Y., Yoon, S. O., Kim, S. G., Roux, P. P. & Blenis, J. Rapamycin differentially inhibits S6Ks and 4E-BP1 to mediate cell-type-specific repression of mRNA translation. Proc. Natl Acad. Sci. USA 105, 17414–17419 (2008). · DOI
  38. Carracedo, A. et al. Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer. J. Clin. Invest. 118, 3065–3074 (2008).
  39. Yu, J., Astrinidis, A., Howard, S. & Henske, E. P. Estradiol and tamoxifen stimulate LAM-associated angiomyolipoma cell growth and activate both genomic and nongenomic signaling pathways. Am. J. Physiol. Lung Cell. Mol. Physiol. 286, L694–L700 (2004). · DOI
  40. Hong, F. et al. mTOR-raptor binds and activates SGK1 to regulate p27 phosphorylation. Mol. Cell 30, 701–711 (2008). · DOI
  41. Xu, J. et al. Mechanistically distinct cancer-associated mTOR activation clusters predict sensitivity to rapamycin. J. Clin. Invest. 126, 3526–3540 (2016). · DOI
  42. Wang, X. & Proud, C. G. The mTOR pathway in the control of protein synthesis. Physiology 21, 362–369 (2006). · DOI · Paper page
  43. Battelli, C. & Cho, D. C. mTOR inhibitors in renal cell carcinoma. Therapy 8, 359–367 (2011). · DOI
  44. Adegoke, O. A., Abdullahi, A. & Tavajohi-Fini, P. mTORC1 and the regulation of skeletal muscle anabolism and mass. Appl. Physiol. Nutr. Metab. 37, 395–406 (2012). · DOI
  45. Chang, G. R. et al. Long-term administration of rapamycin reduces adiposity, but impairs glucose tolerance in high-fat diet-fed KK/HlJ mice. Basic Clin. Pharmacol. Toxicol. 105, 188–198 (2009). · DOI
  46. Fraenkel, M. et al. mTOR inhibition by rapamycin prevents beta-cell adaptation to hyperglycemia and exacerbates the metabolic state in type 2 diabetes. Diabetes 57, 945–957 (2008). · DOI
  47. Pavlakis, M. & Goldfarb-Rumyantzev, A. S. Diabetes after transplantation and sirolimus: what’s the connection? J. Am. Soc. Nephrol. 19, 1255–1256 (2008). · DOI
  48. Kleinert, M. et al. Acute mTOR inhibition induces insulin resistance and alters substrate utilization in vivo. Mol. Metab. 3, 630–641 (2014). · DOI
  49. Yang, S. B. et al. Rapamycin induces glucose intolerance in mice by reducing islet mass, insulin content, and insulin sensitivity. J. Mol. Med. 90, 575–585 (2012). · DOI
  50. Chantranupong, L. et al. The Sestrins interact with GATOR2 to negatively regulate the amino-acid-sensing pathway upstream of mTORC1. Cell Rep. 9, 1–8 (2014). · DOI · Paper page
  51. Wolfson, R. L. et al. KICSTOR recruits GATOR1 to the lysosome and is necessary for nutrients to regulate mTORC1. Nature 543, 438–442 (2017). · DOI
  52. Goorden, S. M. et al. Rheb is essential for murine development. Mol. Cell. Biol. 31, 1672–1678 (2011). · DOI
  53. Groenewoud, M. J. et al. Mammalian target of rapamycin complex I (mTORC1) activity in ras homologue enriched in brain (Rheb)-deficient mouse embryonic fibroblasts. PLoS ONE 8, e81649 (2013). · DOI
  54. Potheraveedu, V. N., Schopel, M., Stoll, R. & Heumann, R. Rheb in neuronal degeneration, regeneration, and connectivity. Biol. Chem. 398, 589–606 (2017). · DOI
  55. Shahani, N. et al. Rheb GTPase regulates beta-secretase levels and amyloid beta generation. J. Biol. Chem. 289, 5799–5808 (2014). · DOI
  56. Delgoffe, G. M. et al. The kinase mTOR regulates the differentiation of helper T cells through the selective activation of signaling by mTORC1 and mTORC2. Nat. Immunol. 12, 295–303 (2011). · DOI
  57. Pollizzi, K. N. et al. mTORC1 and mTORC2 selectively regulate CD8(+) T cell differentiation. J. Clin. Invest. 125, 2090–2108 (2015). · DOI
  58. Knowles, M. A., Hornigold, N. & Pitt, E. Tuberous sclerosis complex (TSC) gene involvement in sporadic tumours. Biochem. Soc. Trans. 31, 597–602 (2003). · DOI
  59. Zhang, H. M., Diaz, V., Walsh, M. E. & Zhang, Y. Moderate lifelong overexpression of tuberous sclerosis complex 1 (TSC1) improves health and survival in mice. Sci. Rep. 7, 834 (2017). · DOI · Paper page
  60. Welsch, M. E. et al. Multivalent small-molecule Pan-RAS inhibitors. Cell 168, 878–889 e829 (2017). · DOI

Cited by

Sorted by citations

See all 88

Metadata

Authors
Mahoney, S. J., Narayan, S., Molz, L., Berstler, L. A., Kang, S. A., Vlasuk, G. P., & Saiah, E.
ORCID
Mahoney, Sarah J.
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2018-02-07
Volume
9
Issue
1
ISSN
2041-1723
DOI
10.1038/s41467-018-03035-z
PMC
PMC5803267
Cited by
88
References
10
Language
en
Licence

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review