Rapamycin

Rapamycin, also known as sirolimus, is a macrolide compound produced by the soil bacterium Streptomyces hygroscopicus. It was discovered in 1975 from a soil sample on Easter Island, also called Rapa Nui. Clinically, rapamycin functions as an immunosuppressant with antiproliferative properties and is used to prevent organ transplant rejection; it and related compounds are studied for cancer and other conditions.

Rapamycin binds the intracellular protein FKBP12 to form a complex that inhibits the mechanistic target of rapamycin complex 1 (mTORC1), a central regulator of cell growth, metabolism, and protein synthesis. Prolonged exposure can affect mTORC2 in some cells. By inhibiting mTOR signaling, rapamycin reduces T-cell proliferation and immune responsiveness.

In transplantation, rapamycin is used to prevent rejection, usually in combination with other immunosuppressants. It is approved for kidney transplant prophylaxis and is used off-label or in regimens for other transplant types. It and its analogs have been explored for certain cancers and for tuberous sclerosis complex–related tumors, with regulatory approvals depending on indication.

Rapamycin is administered orally with variable bioavailability and a long elimination half-life. It is metabolized primarily by hepatic CYP3A4 and is a substrate of P-glycoprotein; therapeutic drug monitoring is common. Side effects include increased infection risk, hyperlipidemia, edema, mouth ulcers, hypertension, anemia, thrombocytopenia, wound-healing impairment, and interstitial pneumonitis; interactions with CYP3A4 inhibitors or inducers are important considerations.

The name derives from Rapa Nui (Easter Island). Analogs include everolimus, temsirolimus, and ridaforolimus (deforolimus); together known as rapalogs. The discovery of rapamycin helped identify the mTOR pathway, a key regulator of growth and aging research.