Rapamycin

Category: other

Aliases: sirolimus

Pharmacological Mechanism

mTORC1 inhibitor (FKBP12 complex); chronic mTORC2 inhibition with sustained dosing.

Half-Life (t½)

PO: 62h

Dosing Guidelines

• PO: Typical 6 (Range: 1–8)

Target Organ Systems

• immune-hematologic
• musculoskeletal

Notes

Off-label for longevity; weekly pulse dosing common.

Pathways It Modulates

• Alzheimer disease (inhibitor) — mTORC1 → ↑autophagy clearance of Aβ + tau (preclinical neuroprotection)
• AMPK energy sensor (activator) — AMPK (indirect — mTORC1 inhibition releases negative feedback)
• Autophagy (macroautophagy) (activator) — mTORC1 inhibition → autophagy ON
• Calcineurin / NFAT T-cell activation (inhibitor) — mTORC1 (parallel arm via same FKBP12 — NOT calcineurin)
• CD4 T-helper differentiation (inhibitor) — mTORC1 → expands Treg, suppresses Teff
• Cellular senescence / SASP / senolytics (inhibitor) — mTOR → gerosuppression (delays onset of senescence; not senolytic)
• cGAS-STING cytosolic DNA sensing → type I IFN (inhibitor) — mTORC1 → cGAS regulation (indirect)
• Circadian clock (inhibitor) — mTORC1 → peripheral clock (translational regulation)
• Hippo / YAP-TAZ signaling (inhibitor) — mTORC1 → YAP cross-talk (TSC2 axis); part of growth-restraint
• Mitophagy (activator) — mTORC1 inhibition → ↑mitophagy + autophagy
• mTOR signaling (inhibitor) — mTORC1 (via FKBP12 complex)
• NAD+ / sirtuin / longevity axis (inhibitor) — mTORC1 (downstream of NAD+/sirtuin axis)
• Neuroinflammation (inhibitor) — mTORC1 → microglial autophagy enhancement
• p53 / MDM2 DNA-damage response (activator) — p53-mTOR cross-talk; rapalogs can stabilize WT p53 in some contexts
• Parkinson disease (inhibitor) — mTORC1 → ↑autophagy clearance of α-synuclein (preclinical)
• PI3K / AKT signaling (inhibitor) — downstream mTORC1 (not PI3K directly)
• Telomere maintenance + shelterin complex (activator) — mTORC1 inhibition → telomere protection via reduced replicative pressure
• Unfolded protein response / ER stress (inhibitor) — UPR (via mTOR damping → ↓ER load)

Chemical Identifiers

• PubChem CID: 5284616
• Formula: C51H79NO13
• Molecular weight: 914.17 g/mol
• InChIKey: QFJCIRLUMZQUOT-HPLJOQBZSA-N
• SMILES: C[C@@H]1CC[C@H]2C[C@@H](/C(=C/C=C/C=C/[C@H](C[C@H](C(=O)[C@@H]([C@@H](/C(=C/[C@H](C(=O)C[C@H](OC(=O)[C@@H]3CCCCN3C(=O)C(=O)[C@@]1(O2)O)[C@H](C)C[C@@H]4CC[C@H]([C@@H](C4)OC)O)C)/C)O)OC)C)C)/C)OC

References

• PMID 32877583