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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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Figures

Fig. 1 DL001 is a selective inhibitor of mTORC1. a Structure of DL001. b, c PC3 cells were treated with rapamycin or DL001 at 0.3–100 nM for 48 h and b the phosphorylation of S6K1 T389 (a mTORC1 substrate), S6 S240/S244 (a readout for mTORC1 activity), and AKT S473 (a mTORC2 substrate) was determined by western blotting; c the inhibition of AKT S473 phosphorylation was plotted (n = 3 biologically independent experiments; *p < 0.005, Sidak’s test following two-way ANOVA). Rapamycin data are plotted in black, DL001 data plotted in red. d–f The IC50 for rapamycin (Rap) and DL001 against d mTORC1 and e mTORC2 was determined using an in vitro assay to measure the phosphorylation of S6 S240/S244 (mTORC1) and AKT S473 (mTORC2) in PC3 lysates treated for 24 h. Rapamycin data are plotted in black, DL001 data plotted in red. f The selectivity of each compound for mTORC1 was calculated from the IC50 (n = 4 biologically independent replicates, three technical replicates each; IC50 was calculated using Prism 7; *p < 0.05, Student’s t-test). g–i Quantitative proteomic analysis was performed on PC3 cells treated for 24 h with 100 nM Rapamycin (Rap) or DL001, or vehicle, and significantly affected (q < 0.05) proteins were analyzed with gProfiler to identify significantly altered KEGG and Reactome categories, which included g ribosome, h translation initiation, and i macroautophagy and lysosome. Error bars represent standard error. Source data are provided as a Source Data file
Fig. 1 DL001 is a selective inhibitor of mTORC1. a Structure of DL001. b, c PC3 cells were treated with rapamycin or DL001 at 0.3–100 nM for 48 h and b the phosphorylation of S6K1 T389 (a mTORC1 substrate), S6 S240/S244 (a readout for mTORC1 activity), and AKT S473 (a mTORC2 substrate) was determined by western blotting; c the inhibition of AKT S473 phosphorylation was plotted (n = 3 biologically independent experiments; *p < 0.005, Sidak’s test following two-way ANOVA). Rapamycin data are plotted in black, DL001 data plotted in red. d–f The IC50 for rapamycin (Rap) and DL001 against d mTORC1 and e mTORC2 was determined using an in vitro assay to measure the phosphorylation of S6 S240/S244 (mTORC1) and AKT S473 (mTORC2) in PC3 lysates treated for 24 h. Rapamycin data are plotted in black, DL001 data plotted in red. f The selectivity of each compound for mTORC1 was calculated from the IC50 (n = 4 biologically independent replicates, three technical replicates each; IC50 was calculated using Prism 7; *p < 0.05, Student’s t-test). g–i Quantitative proteomic analysis was performed on PC3 cells treated for 24 h with 100 nM Rapamycin (Rap) or DL001, or vehicle, and significantly affected (q < 0.05) proteins were analyzed with gProfiler to identify significantly altered KEGG and Reactome categories, which included g ribosome, h translation initiation, and i macroautophagy and lysosome. Error bars represent standard error. Source data are provided as a Source Data fileCC BY · PubMed Central
Fig. 2 DL001 is an FKBP12-dependent mTORC1 inhibitor. a Decreased protein expression of FKBP12 and FKBP51 by shRNA was verified via western blotting. b–d PC3 cells expressing b a nonspecific control shRNA (shCtrl), c shRNA against FKBP12, or d shRNA against FKBP51 were treated with rapamycin or DL001 at 0.3–100 nM for 48 h and the phosphorylation of S6 S240/S244 (a readout for mTORC1 activity) and AKT S473 (a mTORC2 substrate) was determined by western blotting. e–f The inhibition of e S6 S240/S244 phosphorylation and f The inhibition of AKT S473 phosphorylation was plotted (n = 3 biologically independent experiments; statistics for the overall effects of knockdown of FKBP12 or FKBP51 represent the p-value from a two-way ANOVA). Rapamycin data are plotted in black, DL001 data plotted in red; squares represent cells expressing shCtrl, circles cells expressing shFKBP12, and triangles cells expressing shFKBP51. Error bars represent standard error. Source data are provided as a Source Data file
Fig. 2 DL001 is an FKBP12-dependent mTORC1 inhibitor. a Decreased protein expression of FKBP12 and FKBP51 by shRNA was verified via western blotting. b–d PC3 cells expressing b a nonspecific control shRNA (shCtrl), c shRNA against FKBP12, or d shRNA against FKBP51 were treated with rapamycin or DL001 at 0.3–100 nM for 48 h and the phosphorylation of S6 S240/S244 (a readout for mTORC1 activity) and AKT S473 (a mTORC2 substrate) was determined by western blotting. e–f The inhibition of e S6 S240/S244 phosphorylation and f The inhibition of AKT S473 phosphorylation was plotted (n = 3 biologically independent experiments; statistics for the overall effects of knockdown of FKBP12 or FKBP51 represent the p-value from a two-way ANOVA). Rapamycin data are plotted in black, DL001 data plotted in red; squares represent cells expressing shCtrl, circles cells expressing shFKBP12, and triangles cells expressing shFKBP51. Error bars represent standard error. Source data are provided as a Source Data fileCC BY · PubMed Central
Fig. 3 DL001 selectively inhibits mTORC1 in vivo. a–d Protein lysates were prepared from the a liver, b gastrocnemius, and c heart of female C57BL/6J mice treated with vehicle or 13 mg kg−1 DL001 every other day for 20 days, and the phosphorylation of S240/S244 S6 (a readout for mTORC1 activity) and Akt S473, an mTORC2 substrate, was determined by western blotting. d The activity of DL001 and rapamycin against mTORC1 and mTORC2 was determined by quantification of the western blots above and from mice treated in parallel with 8 mg kg−1 rapamycin 30 using NIH ImageJ (n = 4 biologically independent animals per group, *p < 0.05, Tukey–Kramer test following one-way ANOVA). Data from Vehicle-treated mice are plotted with white bars, rapamycin-treated mice with black bars, and DL001-treated mice with red bars. e, f C57BL/6J mice were treated with either vehicle, 8 mg kg−1 rapamycin or 12 mg kg−1 DL001 every other day for 5 weeks. e Quantification of phosphorylated liver proteins in vehicle, rapamycin, and DL001-treated mice (n = 17 vehicle, 16 rapamycin, and 9 DL001-treated biologically independent animals for quantification of phosphorylated S6 and S6K1, 12 vehicle, 10 rapamycin, and 6 DL0001-treated biologically independent animals for quantification of phosphorylated ULK1; Dunnett’s test following one-way ANOVA, *p < 0.05). f The integrity of mTORC2 was determined by immunoprecipitation of Rictor from liver lysate; the immunoprecipitate and lysate were probed with antibodies against the indicated proteins and quantified with NIH ImageJ. mTOR(IP) and RICTOR(IP) refer to the quantification of the mTOR and RICTOR immunoblots from the RICTOR immunoprecipitate (n = 6 vehicle, 5 rapamycin, and 3 DL001-treated biologically independent animals, *p < 0.05, Tukey–Kramer test following one-way ANOVA). e, f Data from Vehicle-treated mice are plotted with white bars, rapamycin-treated mice with black bars, and DL001-treated mice with red bars. Error bars represent standard error. Source data are provided as a Source Data file
Fig. 3 DL001 selectively inhibits mTORC1 in vivo. a–d Protein lysates were prepared from the a liver, b gastrocnemius, and c heart of female C57BL/6J mice treated with vehicle or 13 mg kg−1 DL001 every other day for 20 days, and the phosphorylation of S240/S244 S6 (a readout for mTORC1 activity) and Akt S473, an mTORC2 substrate, was determined by western blotting. d The activity of DL001 and rapamycin against mTORC1 and mTORC2 was determined by quantification of the western blots above and from mice treated in parallel with 8 mg kg−1 rapamycin 30 using NIH ImageJ (n = 4 biologically independent animals per group, *p < 0.05, Tukey–Kramer test following one-way ANOVA). Data from Vehicle-treated mice are plotted with white bars, rapamycin-treated mice with black bars, and DL001-treated mice with red bars. e, f C57BL/6J mice were treated with either vehicle, 8 mg kg−1 rapamycin or 12 mg kg−1 DL001 every other day for 5 weeks. e Quantification of phosphorylated liver proteins in vehicle, rapamycin, and DL001-treated mice (n = 17 vehicle, 16 rapamycin, and 9 DL001-treated biologically independent animals for quantification of phosphorylated S6 and S6K1, 12 vehicle, 10 rapamycin, and 6 DL0001-treated biologically independent animals for quantification of phosphorylated ULK1; Dunnett’s test following one-way ANOVA, *p < 0.05). f The integrity of mTORC2 was determined by immunoprecipitation of Rictor from liver lysate; the immunoprecipitate and lysate were probed with antibodies against the indicated proteins and quantified with NIH ImageJ. mTOR(IP) and RICTOR(IP) refer to the quantification of the mTOR and RICTOR immunoblots from the RICTOR immunoprecipitate (n = 6 vehicle, 5 rapamycin, and 3 DL001-treated biologically independent animals, *p < 0.05, Tukey–Kramer test following one-way ANOVA). e, f Data from Vehicle-treated mice are plotted with white bars, rapamycin-treated mice with black bars, and DL001-treated mice with red bars. Error bars represent standard error. Source data are provided as a Source Data fileCC BY · PubMed Central
Fig. 4 Unlike rapamycin, DL001 does not cause metabolic disruption. a–i C57BL/6J mice were treated with vehicle, 8 mg kg−1 rapamycin, or 12 mg kg−1 DL001 every other day. a Glucose and b pyruvate tolerance tests were performed after 2 or 3 weeks, respectively (n = 18 vehicle, 18 rapamycin, and 9 DL001-treated biologically independent animals; for GTT/PTT, Tukey–Kramer test following two-way repeated-measures ANOVA, a = p < 0.006 vs. vehicle, b = p < 0.006 vs. DL001. For AUC, means with the same letter are not significantly different from each other (Tukey–Kramer test following one-way ANOVA, p < 0.0007)). For GTT/PTT, data from Vehicle-treated mice are plotted with white squares, Rapamycin-treated mice with black squares, and DL001-treated mice with red triangles. c Fasting blood glucose was measured in mice after 4 weeks of treatment (n = 14 vehicle, 16 rapamycin, and 9 DL001-treated biologically independent animals, means with the same letter are not significantly different from each other, Tukey–Kramer test following one-way ANOVA, p < 0.05). d–f Blood was collected after 5 weeks of treatment and plasma levels of d cholesterol, e triglycerides, and f free fatty acids were determined (n = 18 vehicle, 18 rapamycin, and 9 DL001-treated biologically independent animals, means with the same letter are not significantly different from each other, Tukey–Kramer test following one-way ANOVA, p < 0.05). g–i Flow cytometry analysis (expressed as percent of total live cells) of splenocytes collected and isolated after 5 weeks of treatment (n = 18 vehicle, 17 rapamycin, and 9 DL001-treated biologically independent animals, means with the same letter are not significantly different from each other, Tukey–Kramer test following one-way ANOVA, p < 0.05). a–i Data from Vehicle-treated mice are plotted with white bars, rapamycin-treated mice with black bars, and DL001-treated mice with red bars. Error bars represent standard error. Source data are provided as a Source Data file
Fig. 4 Unlike rapamycin, DL001 does not cause metabolic disruption. a–i C57BL/6J mice were treated with vehicle, 8 mg kg−1 rapamycin, or 12 mg kg−1 DL001 every other day. a Glucose and b pyruvate tolerance tests were performed after 2 or 3 weeks, respectively (n = 18 vehicle, 18 rapamycin, and 9 DL001-treated biologically independent animals; for GTT/PTT, Tukey–Kramer test following two-way repeated-measures ANOVA, a = p < 0.006 vs. vehicle, b = p < 0.006 vs. DL001. For AUC, means with the same letter are not significantly different from each other (Tukey–Kramer test following one-way ANOVA, p < 0.0007)). For GTT/PTT, data from Vehicle-treated mice are plotted with white squares, Rapamycin-treated mice with black squares, and DL001-treated mice with red triangles. c Fasting blood glucose was measured in mice after 4 weeks of treatment (n = 14 vehicle, 16 rapamycin, and 9 DL001-treated biologically independent animals, means with the same letter are not significantly different from each other, Tukey–Kramer test following one-way ANOVA, p < 0.05). d–f Blood was collected after 5 weeks of treatment and plasma levels of d cholesterol, e triglycerides, and f free fatty acids were determined (n = 18 vehicle, 18 rapamycin, and 9 DL001-treated biologically independent animals, means with the same letter are not significantly different from each other, Tukey–Kramer test following one-way ANOVA, p < 0.05). g–i Flow cytometry analysis (expressed as percent of total live cells) of splenocytes collected and isolated after 5 weeks of treatment (n = 18 vehicle, 17 rapamycin, and 9 DL001-treated biologically independent animals, means with the same letter are not significantly different from each other, Tukey–Kramer test following one-way ANOVA, p < 0.05). a–i Data from Vehicle-treated mice are plotted with white bars, rapamycin-treated mice with black bars, and DL001-treated mice with red bars. Error bars represent standard error. Source data are provided as a Source Data fileCC BY · PubMed Central
Fig. 5 DL001 corrects mTORC1-mediated signaling and metabolic defects of TSC1−/− cells. a Immortalized mouse embryonic fibroblasts (MEFs) expressing or lacking TSC1 were treated with varying doses of rapamycin or DL001 for 24 h. The phosphorylation of S240/S244 S6 (a readout for mTORC1 activity) and Akt S473, an mTORC2 substrate, was determined by western blotting of protein lysate. b–d MEFs expressing (T1+/+) or lacking TSC1 (TSC1−/−) were treated with vehicle, 100 nM rapamycin, or 100 nM DL001 for 24 h, and the expression of mTORC1 responsive genes involved in b glycolysis, c sterol biosynthesis, and d fatty acid biosynthesis were determined by qPCR (n = 4 biologically independent experiments per condition, means with the same letter are not significantly different from each other, Tukey–Kramer test following one-way ANOVA, p < 0.05). e Protein lysates were prepared from the brain of C57BL/6J mice treated with either vehicle, 8 mg kg−1 rapamycin or 12 mg kg−1 DL001 every other day for 5 weeks, and the phosphorylation of S240/S244 S6 was determined by western blotting (n = 3 vehicle, 4 rapamycin, and 4 DL001-treated biologically independent animals, Tukey–Kramer test following one-way ANOVA, *p < 0.05). Data from Vehicle-treated mice are plotted with white bars, rapamycin-treated mice with black bars, and DL001-treated mice with red bars. Error bars represent standard error. Source data are provided as a Source Data file
Fig. 5 DL001 corrects mTORC1-mediated signaling and metabolic defects of TSC1−/− cells. a Immortalized mouse embryonic fibroblasts (MEFs) expressing or lacking TSC1 were treated with varying doses of rapamycin or DL001 for 24 h. The phosphorylation of S240/S244 S6 (a readout for mTORC1 activity) and Akt S473, an mTORC2 substrate, was determined by western blotting of protein lysate. b–d MEFs expressing (T1+/+) or lacking TSC1 (TSC1−/−) were treated with vehicle, 100 nM rapamycin, or 100 nM DL001 for 24 h, and the expression of mTORC1 responsive genes involved in b glycolysis, c sterol biosynthesis, and d fatty acid biosynthesis were determined by qPCR (n = 4 biologically independent experiments per condition, means with the same letter are not significantly different from each other, Tukey–Kramer test following one-way ANOVA, p < 0.05). e Protein lysates were prepared from the brain of C57BL/6J mice treated with either vehicle, 8 mg kg−1 rapamycin or 12 mg kg−1 DL001 every other day for 5 weeks, and the phosphorylation of S240/S244 S6 was determined by western blotting (n = 3 vehicle, 4 rapamycin, and 4 DL001-treated biologically independent animals, Tukey–Kramer test following one-way ANOVA, *p < 0.05). Data from Vehicle-treated mice are plotted with white bars, rapamycin-treated mice with black bars, and DL001-treated mice with red bars. Error bars represent standard error. Source data are provided as a Source Data fileCC BY · PubMed Central

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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

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 ›

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