ATP-competitive mTOR inhibitors

Drug · 6 studies in the Atlas

Torin1, AZD8055 and relatives occupy the mTOR active site directly, inhibiting both complexes.

Drugs that block mTOR's engine instead of getting in its way. Drugs that block mTOR's engine instead of getting in its way.

Designed as a research answer to rapamycin's incompleteness, then developed clinically. Because they compete with ATP at the catalytic site they do not need FKBP12, they suppress 4E-BP1 phosphorylation that rapalogs leave standing, and they hit mTORC2 as well – which is both their advantage and their toxicity problem.

TL;DR. ATP-competitive mTOR inhibitors appears in 6 curated studies in Oliver's mTOR Atlas: 6 at the molecular level (cells, biochemistry, structure). No study in people is recorded for it in the Atlas yet. It has 2 interactions in the curated pathway model.

Which mTOR drugs are in development now, and why: mTOR drugs in development →

In the pathway model

2 interactions in the curated mTOR pathway model. Each row is a claim with the evidence behind it; the evidence code is the kind of study, not its quality.

Interaction	Mechanism	Evidence	Studies
ATP-competitive mTOR inhibitors inhibits mTORC1 mechanism: competitive-inhibition · this link in full · on the map table	Torin sits in the spot where mTOR holds its energy molecule ATP, so it shuts the kinase down whatever the kinase is about to modify. Rapamycin leaves part of mTORC1's work running; Torin does not, which is how researchers learned how much rapamycin had been missing. This comes from cell-culture work, not from patients. Occupies the mTOR active site in competition with ATP, so inhibition does not depend on obstructing substrate access and is not partial in the way rapalog inhibition is. Occupies the mTOR active site in competition with ATP, so inhibition does not depend on obstructing substrate access and is not partial in the way rapalog inhibition is. Holds under: Cell-line pharmacology. Clinical development of this class has been limited by toxicity attributed to simultaneous mTORC2 inhibition, which is precisely what the bi-steric design tries to avoid. plausible in people, not shown directly · settled in the literature	M	THO2009, FEL2009, CHR2009, JAN2010, ROD2011, GAR2009
ATP-competitive mTOR inhibitors inhibits mTORC2 mechanism: competitive-inhibition · this link in full · on the map table	mTORC1 and mTORC2 use the same ATP-binding pocket, so a drug that blocks the pocket hits both and cannot choose. That is thought to explain why this class of drugs causes more metabolic and immune side effects than rapamycin-type drugs, but the size of that effect has only been seen in cell studies and has not been measured in patients. The same active site is present in both complexes, so an ATP-competitive inhibitor cannot distinguish them. The same active site is present in both complexes, so an ATP-competitive inhibitor cannot distinguish them. Holds under: Explains the metabolic and immunological toxicity of this class relative to rapalogs; the magnitude in patients is not established from these cell-line studies. plausible in people, not shown directly · settled in the literature	M	THO2009, FEL2009, JAN2010, ROD2011, GAR2009

Evidence at a glance

Evidence	What it means	Studies
M	Molecular — cells, biochemistry, structure	6

No direct human evidence in the Atlas for this entity yet — everything below rests on animal or molecular work.

Studies

Year	Evidence	Study
2011	M	mTOR kinase inhibition causes feedback-dependent biphasic regulation of AKT signaling ROD2011 mTOR kinase inhibition triggers feedback-dependent biphasic AKT reactivation, informing resistance.
2010	M	Effective and selective targeting of leukemia cells using a TORC1/2 kinase inhibitor JAN2010 The ATP-competitive TORC1/2 inhibitor PP242 selectively kills leukemia cells, with much weaker effects on the proliferation and function of normal lymphocytes.
2009	M	Active-site inhibitors of mTOR target rapamycin-resistant outputs of mTORC1 and mTORC2 FEL2009 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.
2009	M	An ATP-competitive mammalian target of rapamycin inhibitor reveals rapamycin-resistant functions of mTORC1 THO2009 Dropped a bombshell: rapamycin does NOT fully block mTORC1. Using Torin1 (which jams the active site directly), the authors showed rapamycin leaves important mTORC1 jobs running - notably 4E-BP1 phosphorylation and autophagy suppression. This reframed a decade of rapamycin experiments and launched the search for complete inhibitors.
2009	M	AZD8055 is a potent, selective, and orally bioavailable ATP-competitive mammalian target of rapamycin kinase inhibitor with in vitro and in vivo antitumor activity CHR2009 AZD8055, an ATP-competitive mTOR kinase inhibitor, blocks both mTORC1 and mTORC2 (rapamycin-resistant outputs).
2009	M	Ku-0063794 is a specific inhibitor of the mammalian target of rapamycin (mTOR) GAR2009 Ku-0063794 is a specific ATP-competitive mTOR inhibitor blocking mTORC1 and mTORC2.

Related entities

mTORC1 5 mTORC2 4PP242Rapamycin 2 Akt/PKB 2 4E-BP1 2 SGK1 1 Torin1 1

Cite this page

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Barton, O. (2026). ATP-competitive mTOR inhibitors [Entity page]. In Oliver's mTOR Atlas [Data set]. https://mtor-atlas.org/drug/atp-competitive-mtor-inhibitors/ · Dataset DOI 10.5281/zenodo.22059963

@misc{atlas_drug_atp_competitive_mtor_inhibitors,
  author       = {Barton, Oliver},
  title        = {{Oliver's mTOR Atlas}: ATP-competitive mTOR inhibitors},
  howpublished = {Entity page in a data set},
  year         = {2026},
  url          = {https://mtor-atlas.org/drug/atp-competitive-mtor-inhibitors/},
  doi          = {10.5281/zenodo.22059963}
}

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