Bi-steric mTORC1-selective inhibitors

Drug · 1 studies in the Atlas

Bivalent compounds (e.g. RMC-5552) engaging both an FKBP12-dependent site and the active site, giving deeper mTORC1 inhibition with selectivity over mTORC2.

A newer design: deep inhibition of one complex only. A newer design: deep inhibition of one complex only.

The attempt to have it both ways: the depth of an active-site inhibitor with the mTORC1 selectivity of a rapalog, so that 4E-BP1 is actually suppressed without incurring the mTORC2-dependent metabolic toxicity. RMC-5552 has completed a phase 1 trial in advanced solid tumours (SCH2025): a safety and pharmacodynamic result, not an efficacy verdict.

TL;DR. Bi-steric mTORC1-selective inhibitors appears in 1 curated study in Oliver's mTOR Atlas: 1 in people (1 human study). It has 1 interaction in the curated pathway model.

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

In the pathway model

1 interaction 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
Bi-steric mTORC1-selective inhibitors inhibits mTORC1 mechanism: competitive-inhibition · this link in full · on the map table	A two-part drug grips mTORC1 at two places at once, which blocks it more completely than rapamycin-type drugs. So far only a first safety trial in people with advanced tumours has reported on it. A bivalent molecule engages an FKBP12-dependent site and the active site simultaneously, producing deeper mTORC1 inhibition than a rapalog while sparing mTORC2. A bivalent molecule engages an FKBP12-dependent site and the active site simultaneously, producing deeper mTORC1 inhibition than a rapalog while sparing mTORC2. Holds under: Phase 1 in advanced solid tumours – a safety and pharmacodynamic result, not an efficacy verdict. Directness is graded indirect because, like rapalogs, the mechanism requires FKBP12. Consensus is emerging: one trial. plausible in people, not shown directly · emerging, few independent studies	H	SCH2025

Evidence at a glance

Evidence	What it means	Studies
H	Human study	1

Studies

Year	Evidence	Study
2025	H	The Bi-steric, mTORC1-Selective Inhibitor, RMC-5552, in Advanced Solid Tumors: A Phase 1 Trial SCH2025 First-in-human, open-label dose-escalation trial (n=57, advanced solid tumors, no comparator arm) of a bi-steric mTORC1-selective inhibitor. Treatment-related hyperglycemia was low (4%) and not dose-limiting, alongside a 64% disease control rate. Because the trial was uncontrolled and made no head-to-head comparison against rapamycin or an ATP-site inhibitor, this is encouraging early clinical evidence consistent with the hypothesis that sparing mTORC2 reduces metabolic toxicity -- it does not establish mTORC2 sparing as the cause.

Related entities

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Barton, O. (2026). Bi-steric mTORC1-selective inhibitors [Entity page]. In Oliver's mTOR Atlas [Data set]. https://mtor-atlas.org/drug/bi-steric-mtorc1-selective-inhibitors/ · Dataset DOI 10.5281/zenodo.22059963

@misc{atlas_drug_bi_steric_mtorc1_selective_inhibitors,
  author       = {Barton, Oliver},
  title        = {{Oliver's mTOR Atlas}: Bi-steric mTORC1-selective inhibitors},
  howpublished = {Entity page in a data set},
  year         = {2026},
  url          = {https://mtor-atlas.org/drug/bi-steric-mtorc1-selective-inhibitors/},
  doi          = {10.5281/zenodo.22059963}
}

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