Active-site inhibitors of mTOR target rapamycin-resistant outputs of mTORC1 and mTORC2

Feldman ME, Apsel B, Uotila A, Loewith R, Knight ZA, Ruggero D, Shokat KM · 2009 · PLoS Biology · Atlas ID FEL2009

What this study shows

The parallel discovery to Thoreen 2009 (same year), from the Shokat lab. Their TORKinibs (PP242, PP30) block mTOR's active site, hitting both complexes and shutting down cap-dependent translation that rapamycin misses. Together these two papers established a whole new drug class beyond rapamycin.

Abstract

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The mammalian target of rapamycin (mTOR) regulates cell growth and survival by integrating nutrient and hormonal signals. These signaling functions are distributed between at least two distinct mTOR protein complexes: mTORC1 and mTORC2. mTORC1 is sensitive to the selective inhibitor rapamycin and activated by growth factor stimulation via the canonical phosphoinositide 3-kinase (PI3K)-->Akt-->mTOR pathway. Activated mTORC1 kinase up-regulates protein synthesis by phosphorylating key regulators of mRNA translation. By contrast, mTORC2 is resistant to rapamycin.

Read the full abstract on PubMed →

At a glance

Evidence type	M Molecular — cells, biochemistry, structure Marked M because it is molecular or in-vitro work (model: Mouse fibroblasts + primary cells) rather than a whole-organism health-outcome study. That is often exactly where causal biology gets established -- the code says which system the finding was shown in, and nothing about how good the work is.
Study type	5 - Mechanistic / In Vitro
Model system	Mouse fibroblasts + primary cells
Journal	PLoS Biology
Year	2009
Peer reviewed	Yes
Record last updated	2026-10-01
Source	DOI 10.1371/journal.pbio.1000038 · PMID 19209957 · Free full text (PMC2637922)

Extracted findings

These fields were extracted from the paper with AI assistance and have not been checked against the source. Read them as a pointer into the paper, not as curated claims; where they disagree with the curated summary above, the curated summary stands.

Intervention	ATP-competitive mTOR active-site inhibitors (vs rapamycin)
Target	mTORC1 & mTORC2
Model	Mouse fibroblasts + primary cells
Effect	Active-site inhibitors block rapamycin-resistant outputs of mTORC1/2 (e.g. 4E-BP1), unlike rapamycin

In the Atlas

Links in the pathway map

Supports mTORC1 inhibits 4E-BP1
Supports ATP-competitive mTOR inhibitors inhibits mTORC1
Supports ATP-competitive mTOR inhibitors inhibits mTORC2

Learn the biology

Want to understand the biology behind this study? → Challenge 02: Why rapamycin does not switch mTORC1 off

Cite this paper

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Feldman, M. E., Apsel, B., Uotila, A., Loewith, R., Knight, Z. A., Ruggero, D., & Shokat, K. M. (2009). Active-site inhibitors of mTOR target rapamycin-resistant outputs of mTORC1 and mTORC2. PLoS Biology. https://doi.org/10.1371/journal.pbio.1000038

@article{FEL2009,
  author       = {Feldman, M. E. and Apsel, B. and Uotila, A. and Loewith, R. and Knight, Z. A. and Ruggero, D. and Shokat, K. M.},
  title        = {{Active-site inhibitors of mTOR target rapamycin-resistant outputs of mTORC1 and mTORC2}},
  journal      = {PLoS Biology},
  year         = {2009},
  doi          = {10.1371/journal.pbio.1000038},
  note         = {PMID: 19209957},
}

Cite this Atlas record

The record is the Atlas's own work — the evidence label, the extracted findings and the links. It is cited as part of the dataset, not as the paper.

Barton, O. (2026). Oliver's mTOR Atlas (record FEL2009) [Data set]. https://mtor-atlas.org/study/FEL2009/ · Dataset DOI 10.5281/zenodo.22059963

@misc{atlas_FEL2009,
  author       = {Barton, Oliver},
  title        = {{Oliver's mTOR Atlas}, record FEL2009},
  howpublished = {Data set},
  year         = {2026},
  url          = {https://mtor-atlas.org/study/FEL2009/},
  doi          = {10.5281/zenodo.22059963}
}

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