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A novel rapamycin analog is highly selective for mTORC1 in vivo

Schreiber, Katherine H., Arriola Apelo, Sebastian I., Yu, Deyang, Brinkman, Jacqueline A., Velarde, Michael C., Syed, Faizan A., Liao, Chen-Yu, Baar, Emma L., Carbajal, Kathryn A., Sherman, Dawn S., Ortiz, Denise, Brunauer, Regina, Yang, Shany E., Tzannis, Stelios T., Kennedy, Brian K., Lamming, Dudley W.·2019·Nature Communications
DOI 10.1038/s41467-019-11174-0PMC PMC6642166
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Abstract

Rapamycin, an inhibitor of mechanistic Target Of Rapamycin Complex 1 (mTORC1), extends lifespan and shows strong potential for the treatment of age-related diseases. However, rapamycin exerts metabolic and immunological side effects mediated by off-target inhibition of a second mTOR-containing complex, mTOR complex 2. Here, we report the identification of DL001, a FKBP12-dependent rapamycin analog 40x more selective for mTORC1 than rapamycin. DL001 inhibits mTORC1 in cell culture lines and in vivo in C57BL/6J mice, in which DL001 inhibits mTORC1 signaling without impairing glucose homeostasis and with substantially reduced or no side effects on lipid metabolism and the immune system. In cells, DL001 efficiently represses elevated mTORC1 activity and restores normal gene expression to cells lacking a functional tuberous sclerosis complex. Our results demonstrate that highly selective pharmacological inhibition of mTORC1 can be achieved in vivo, and that selective inhibition of mTORC1 significantly reduces the side effects associated with conventional rapalogs.

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  1. Bjedov, I. et al. Mechanisms of life span extension by rapamycin in the fruit fly Drosophila melanogaster. Cell Metab. 11, 35–46 (2010). · DOI · Paper page
  2. Powers, R. W. 3rd, Kaeberlein, M., Caldwell, S. D., Kennedy, B. K. & Fields, S. Extension of chronological life span in yeast by decreased TOR pathway signaling. Genes Dev. 20, 174–184 (2006). · DOI · Paper page
  3. Majumder, S. et al. Lifelong rapamycin administration ameliorates age-dependent cognitive deficits by reducing IL-1beta and enhancing NMDA signaling. Aging Cell 11, 326–335 (2012). · DOI
  4. Dai, D. F. et al. Altered proteome turnover and remodeling by short-term caloric restriction or rapamycin rejuvenate the aging heart. Aging Cell 13, 529–539 (2014). · DOI
  5. Wilkinson, J. E. et al. Rapamycin slows aging in mice. Aging Cell 11, 675–682 (2012). · DOI · Paper page
  6. Urfer, S. R. et al. A randomized controlled trial to establish effects of short-term rapamycin treatment in 24 middle-aged companion dogs. Geroscience 39, 117–127 (2017). · DOI · Paper page
  7. Lelegren, M., Liu, Y., Ross, C., Tardif, S. & Salmon, A. B. Pharmaceutical inhibition of mTOR in the common marmoset: effect of rapamycin on regulators of proteostasis in a non-human primate. Pathobiol. Aging Age Relat. Dis. 6, 31793 (2016). · DOI
  8. Trelinska, J. et al. Complications of mammalian target of rapamycin inhibitor anticancer treatment among patients with tuberous sclerosis complex are common and occasionally life-threatening. Anti-cancer drugs 26, 437–442 (2015). · DOI · Paper page
  9. Lamming, D. W., Ye, L., Sabatini, D. M. & Baur, J. A. Rapalogs and mTOR inhibitors as anti-aging therapeutics. J. Clin. Invest 123, 980–989 (2013). · DOI · Paper page
  10. Kennedy, B. K. & Lamming, D. W. The Mechanistic Target of Rapamycin: The Grand ConducTOR of Metabolism and Aging. Cell Metab. 23, 990–1003 (2016). · DOI · Paper page
  11. Verges, B. & Cariou, B. mTOR inhibitors and diabetes. Diabetes Res Clin. Pr. 110, 101–108 (2015). · DOI
  12. 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
  13. Hurvitz, S. A. et al. Combination of everolimus with trastuzumab plus paclitaxel as first-line treatment for patients with HER2-positive advanced breast cancer (BOLERO-1): a phase 3, randomised, double-blind, multicentre trial. Lancet Oncol. 16, 816–829 (2015). · DOI
  14. Yao, J. C. et al. Everolimus for the treatment of advanced, non-functional neuroendocrine tumours of the lung or gastrointestinal tract (RADIANT-4): a randomised, placebo-controlled, phase 3 study. Lancet 387, 968–977 (2016). · DOI
  15. Arriola Apelo, S. I., Pumper, C. P., Baar, E. L., Cummings, N. E. & Lamming, D. W. Intermittent Administration of Rapamycin Extends the Life Span of Female C57BL/6J Mice. J. Gerontol. A Biol. Sci. Med Sci. 71, 876–881 (2016). · DOI
  16. Kraig, E. et al. A randomized control trial to establish the feasibility and safety of rapamycin treatment in an older human cohort: Immunological, physical performance, and cognitive effects. Exp. Gerontol. 105, 53–69 (2018). · DOI · Paper page
  17. Miller, R. A. et al. Rapamycin-mediated lifespan increase in mice is dose and sex dependent and metabolically distinct from dietary restriction. Aging Cell 13, 468–477 (2014). · DOI
  18. Bitto, A. et al. Transient rapamycin treatment can increase lifespan and healthspan in middle-aged mice. eLife 5, e16351 (2016). · DOI · Paper page
  19. Dumas S. N., Lamming D. W. Next generation strategies for geroprotection via mTORC1 inhibition. J. Gerontol. A Biol. Sci. Med. Sci. glz056 https://doi.org/10.1093/gerona/glz056 (2019). [Epub ahead of print] · DOI
  20. Sarbassov, D. D. et al. Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr. Biol. 14, 1296–1302 (2004). · DOI · Paper page
  21. 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
  22. Zeng, Z. et al. Rapamycin derivatives reduce mTORC2 signaling and inhibit AKT activation in AML. Blood 109, 3509–3512 (2007). · DOI
  23. Schreiber, K. H. et al. Rapamycin-mediated mTORC2 inhibition is determined by the relative expression of FK506-binding proteins. Aging Cell 14, 265–273 (2015). · DOI
  24. Sarbassov, D. D. et al. Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Mol. Cell 22, 159–168 (2006). · DOI · Paper page
  25. Liang, J., Choi, J. & Clardy, J. Refined structure of the FKBP12-rapamycin-FRB ternary complex at 2.2 A resolution. Acta Crystallogr D. Biol. Crystallogr 55, 736–744 (1999). · DOI · Paper page
  26. Marz, A. M., Fabian, A. K., Kozany, C., Bracher, A. & Hausch, F. Large FK506-binding proteins shape the pharmacology of rapamycin. Mol. Cell Biol. 33, 1357–1367 (2013). · DOI · Paper page
  27. Harrington, L. S. et al. The TSC1–2 tumor suppressor controls insulin-PI3K signaling via regulation of IRS proteins. J. Cell Biol. 166, 213–223 (2004). · DOI
  28. Hsu, P. P. et al. The mTOR-regulated phosphoproteome reveals a mechanism of mTORC1-mediated inhibition of growth factor signaling. Science 332, 1317–1322 (2011). · DOI · Paper page
  29. Tang, Y. et al. Adipose tissue mTORC2 regulates ChREBP-driven de novo lipogenesis and hepatic glucose metabolism. Nat. Commun. 7, 11365 (2016). · DOI
  30. Kumar, A. et al. Muscle-specific deletion of rictor impairs insulin-stimulated glucose transport and enhances Basal glycogen synthase activity. Mol. Cell Biol. 28, 61–70 (2008). · DOI
  31. Kumar, A. et al. Fat cell-specific ablation of rictor in mice impairs insulin-regulated fat cell and whole-body glucose and lipid metabolism. Diabetes 59, 1397–1406 (2010). · DOI
  32. Lamming, D. W. et al. Depletion of Rictor, an essential protein component of mTORC2, decreases male lifespan. Aging Cell 13, 911–917 (2014). · DOI · Paper page
  33. de Wit, D. et al. Everolimus pharmacokinetics and its exposure-toxicity relationship in patients with thyroid cancer. Cancer Chemother. Pharm. 78, 63–71 (2016). · DOI
  34. Kovarik, J. M. et al. Everolimus in de novo cardiac transplantation: pharmacokinetics, therapeutic range, and influence on cyclosporine exposure. J. Heart Lung Transpl. 22, 1117–1125 (2003). · DOI
  35. Lamming, D. W. et al. Young and old genetically heterogeneous HET3 mice on a rapamycin diet are glucose intolerant but insulin sensitive. Aging Cell 12, 712–718 (2013). · DOI
  36. Lamming, D. W. & Sabatini, D. M. A Central role for mTOR in lipid homeostasis. Cell Metab. 18, 465–469 (2013). · DOI
  37. Peterson, T. R. et al. mTOR complex 1 regulates lipin 1 localization to control the SREBP pathway. Cell 146, 408–420 (2011). · DOI
  38. Soliman, G. A., Acosta-Jaquez, H. A. & Fingar, D. C. mTORC1 inhibition via rapamycin promotes triacylglycerol lipolysis and release of free fatty acids in 3T3-L1 adipocytes. Lipids 45, 1089–1100 (2010). · DOI
  39. Chakrabarti, P. et al. Insulin inhibits lipolysis in adipocytes via the evolutionarily conserved mTORC1-Egr1-ATGL-mediated pathway. Mol. Cell Biol. 33, 3659–3666 (2013). · DOI
  40. Mahe, E. et al. Cutaneous adverse events in renal transplant recipients receiving sirolimus-based therapy. Transplantation 79, 476–482 (2005). · DOI
  41. Goldberg, E. L. et al. Lifespan-extending caloric restriction or mTOR inhibition impair adaptive immunity of old mice by distinct mechanisms. Aging Cell 14, 130–138 (2015). · DOI
  42. Goldberg, E. L., Smithey, M. J., Lutes, L. K., Uhrlaub, J. L. & Nikolich-Zugich, J. Immune memory-boosting dose of rapamycin impairs macrophage vesicle acidification and curtails glycolysis in effector CD8 cells, impairing defense against acute infections. J. Immunol. 193, 757–763 (2014). · DOI · Paper page
  43. Wang, Y. et al. Regulatory T cells require mammalian target of rapamycin signaling to maintain both homeostasis and alloantigen-driven proliferation in lymphocyte-replete mice. J. Immunol. 186, 2809–2818 (2011). · DOI
  44. Makki, K. et al. Beneficial metabolic effects of rapamycin are associated with enhanced regulatory cells in diet-induced obese mice. PLoS ONE 9, e92684 (2014). · DOI
  45. Kwiatkowski, D. J. & Manning, B. D. Tuberous sclerosis: a GAP at the crossroads of multiple signaling pathways. Hum. Mol. Genet 14(Spec No. 2), R251–R258 (2005). · DOI · Paper page
  46. Yang, J. et al. Renal tumours in a Tsc2( + /-) mouse model do not show feedback inhibition of Akt and are effectively prevented by rapamycin. Oncogene 34, 922–931 (2015). · DOI
  47. Krueger, D. A. et al. Everolimus long-term safety and efficacy in subependymal giant cell astrocytoma. Neurology 80, 574–580 (2013). · DOI
  48. Kwiatkowski, D. J. et al. Response to everolimus is seen in TSC-associated SEGAs and angiomyolipomas independent of mutation type and site in TSC1 and TSC2. Eur. J. Hum. Genet. : EJHG 23, 1665–1672 (2015). · DOI
  49. Bissler, J. J. et al. Everolimus long-term use in patients with tuberous sclerosis complex: Four-year update of the EXIST-2 study. PLoS One 12, e0180939 (2017). · DOI · Paper page
  50. Krueger, D. A. et al. Long-term treatment of epilepsy with everolimus in tuberous sclerosis. Neurology 87, 2408–2415 (2016). · DOI · Paper page
  51. Duvel, K. et al. Activation of a metabolic gene regulatory network downstream of mTOR complex 1. Mol. Cell 39, 171–183 (2010). · DOI · Paper page
  52. Li, K. et al. Rheb1 deletion in myeloid cells aggravates OVA-induced allergic inflammation in mice. Sci. Rep. 7, 42655 (2017). · DOI
  53. Yang, W. et al. Genetic deletion of Rheb1 in the brain reduces food intake and causes hypoglycemia with altered peripheral metabolism. Int J. Mol. Sci. 15, 1499–1510 (2014). · DOI
  54. Tian, Q. et al. RHEB1 insufficiency in aged male mice is associated with stress-induced seizures. Geroscience 39, 557–570 (2017). · DOI
  55. Frey, J. W., Jacobs, B. L., Goodman, C. A. & Hornberger, T. A. A role for Raptor phosphorylation in the mechanical activation of mTOR signaling. Cell Signal 26, 313–322 (2014). · DOI
  56. Crino, P. B. Focal brain malformations: a spectrum of disorders along the mTOR cascade. Novartis Found. Symp. 288, 260–272 (2007). discussion 272–281. · DOI
  57. Ye, L., Varamini, B., Lamming, D. W., Sabatini, D. M. & Baur, J. A. Rapamycin has a biphasic effect on insulin sensitivity in C2C12 myotubes due to sequential disruption of mTORC1 and mTORC2. Front Genet 3, 177 (2012). · DOI
  58. Cummings, N. E. et al. Restoration of metabolic health by decreased consumption of branched-chain amino acids. J. Physiol. 596, 623–645 (2018). · DOI
  59. Ritchie, M. E. et al. limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res 43, e47 (2015). · DOI · Paper page

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Metadata

Authors
Schreiber, K. H., Arriola Apelo, S. I., Yu, D., Brinkman, J. A., Velarde, M. C., Syed, F. A., Liao, C.-Y., Baar, E. L., Carbajal, K. A., Sherman, D. S., Ortiz, D., Brunauer, R., Yang, S. E., Tzannis, S. T., Kennedy, B. K., & Lamming, D. W.
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2019-07-19
Volume
10
Issue
1
ISSN
2041-1723
DOI
10.1038/s41467-019-11174-0
PMC
PMC6642166
Cited by
177
References
11
Language
en
Licence
Funders
  • American Diabetes Association (1-16-PMF-001)
  • American Heart Association (17PRE33410983)
  • U.S. Department of Health & Human Services | NIH | National Cancer Institute (P30CA014520)
  • U.S. Department of Health & Human Services | NIH | National Center for Advancing Translational Sciences (UL1TR002373)
  • UW | School of Medicine and Public Health, University of Wisconsin-Madison
  • U.S. Department of Health & Human Services | NIH | National Institute on Aging (R01AG056771, R01AG062328)
  • Aeonian Pharmaceuticals

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