FKBP12rapamycin

FKBP12-rapamycin refers to the ternary complex formed by the immunophilin FKBP12 and the macrolide antibiotic rapamycin (sirolimus). FKBP12 is a small cytosolic protein that binds rapamycin with high affinity, and the resulting complex acts as a specific inhibitor of the mechanistic target of rapamycin complex 1 (mTORC1). In humans, FKBP12 is encoded by the FKBP1A gene.

The FKBP12-rapamycin complex binds to the FRB domain of mTOR, forming a ternary assembly that allosterically inhibits mTORC1 kinase activity. This leads to reduced phosphorylation of downstream targets such as S6K1 and 4E-BP1, resulting in decreased cap-dependent translation, lowered protein synthesis, and inhibited cell growth and proliferation, while autophagy can be promoted in certain contexts. Prolonged exposure can affect mTOR complex 2 in some cells, but rapamycin is primarily viewed as an mTORC1 inhibitor.

Clinically and in research, rapamycin is used as an immunosuppressant to prevent organ transplant rejection and as an anti-proliferative agent in certain cancers and tuberous sclerosis complex–related tumors. Rapamycin analogs, known as rapalogs (for example everolimus and temsirolimus), extend these therapeutic applications and share the FKBP12-dependent mechanism. In the laboratory, the FKBP12-rapamycin complex is utilized to study mTOR signaling, cell growth, and autophagy, as well as to probe the biology of rapamycin-sensitive pathways.

Common adverse effects include immunosuppression-related infection risk, hyperlipidemia, edema, wound-healing impairment, mouth ulcers, and metabolic disturbances. The drug is metabolized mainly by hepatic cytochrome P450 3A4 and can have significant drug interactions.