What are mTOR inhibitors? The full list, by mechanism
mTOR inhibitors fall into three main mechanistic classes. Rapalogs (rapamycin/sirolimus and its analogs everolimus, temsirolimus, ridaforolimus) bind FKBP12 and allosterically block mTORC1 – the original class, in clinical use since 1999. ATP-competitive inhibitors ("TORKinibs": Torin1, PP242, AZD8055, sapanisertib) jam the kinase's active site directly, blocking mTORC1 and mTORC2 – more complete inhibition, but less selective. Bi-steric inhibitors (RMC-6272, RMC-5552) are the newest class. They shut down mTORC1 completely, including 4E-BP1, which rapamycin cannot, while sparing mTORC2 far better than the ATP-competitive drugs, with roughly 25-fold selectivity rather than absolute sparing. A related group, dual PI3K/mTOR inhibitors (dactolisib, also called BEZ235 or RTB101, and gedatolisib), blocks the ATP site of both mTOR and PI3K.
Rapalogs – allosteric, FKBP12-dependent, mTORC1-selective
- VEZ1975 M – rapamycin (then "AY-22,989") was first isolated from Streptomyces hygroscopicus, a soil bacterium collected on Rapa Nui (Easter Island) – the parent compound of every rapalog since.
- HUD2007 H – temsirolimus (CCI-779, an IV rapalog) extended median overall survival to 10.9 vs 7.3 months over interferon alfa in poor-prognosis metastatic kidney cancer – the trial that made rapalogs an oncology drug class, not just a transplant drug.
- BAS2012 H – everolimus (RAD001, an oral rapalog) added to endocrine therapy roughly doubled progression-free survival in hormone-resistant advanced breast cancer (n=724 phase 3 RCT).
ATP-competitive inhibitors ("TORKinibs") – hit both complexes
- THO2009 M – using Torin1, a true ATP-competitive inhibitor, this study showed rapamycin actually leaves some mTORC1 jobs running (notably 4E-BP1 phosphorylation) – the discovery that motivated building TORKinibs in the first place, for more complete mTORC1 blockade.
TORKinibs block the shared catalytic site both complexes use, so they inhibit mTORC1 and mTORC2 together – more complete, but harder to dose without hitting mTORC2-dependent side effects.
Dual PI3K/mTOR inhibitors: hit mTOR and PI3K together
Dactolisib (BEZ235, later developed as RTB101) and gedatolisib are ATP-competitive inhibitors of both mTOR and class I PI3K, the kinase just upstream of Akt. They block mTORC1, mTORC2 and PI3K at once, so they are the broadest class. RTB101 is the drug tested in the large phase 3 trial MAN2021 (see the side-effects page).
Bi-steric inhibitors – the newest class
- MEN2023 A – RMC-6272, a bi-steric molecule with >25-fold selectivity for mTORC1 over mTORC2, completely suppresses mTORC1 – including 4E-BP1, the substrate rapamycin itself can't fully block – while largely sparing mTORC2.
- SCH2025 H – the first human trial (n=57, advanced solid tumors) of a bi-steric mTORC1-selective inhibitor; treatment-related hyperglycemia was reported, showing even this more selective class isn't side-effect-free.
The idea goes back to RapaLink-1 (2016), which joins rapamycin to an ATP-site inhibitor in one molecule and was the first of these third-generation (bivalent) mTOR inhibitors.
Where this connects to the Atlas's open questions
Whether higher mTORC1 selectivity actually delivers rapamycin's longevity benefit without its metabolic cost is untested in humans at aging-relevant doses – see the open question on mTORC1-selective, mTORC2-sparing dosing.
Related entities
Thank you. Your answer was counted anonymously.