Sirolimus

Sirolimus, also known as rapamycin, is a macrocyclic lactone antibiotic produced by bacteria Streptomyces hygroscopicus, which was isolated from the soil of the Vai Atari region of Rapa Nui (Easter Island). It was first isolated and identified as an antifungal agent with potent anticandida activity; however, after its potent antitumor and immunosuppressive activities were later discovered, it was extensively investigated as an immunosuppressive and antitumour agent. Its primary mechanism of action is the inhibition of the mammalian target of rapamycin (mTOR), which is a serine/threonine-specific protein kinase that regulates cell growth, proliferation, and survival. mTOR is an important therapeutic target for various diseases, as it was shown to regulate longevity and maintain normal glucose homeostasis. Targeting mTOR received more attention especially in cancer, as mTOR signalling pathways are constitutively activated in many types of human cancer. Sirolimus was first approved by the FDA in 1999 for the prophylaxis of organ rejection in patients aged 13 years and older receiving renal transplants. In November 2000, the drug was recognized by the European Agency as an alternative to calcineurin antagonists for maintenance therapy with corticosteroids. In May 2015, the FDA approved sirolimus for the treatment of patients with lymphangioleiomyomatosis. In November 2021, albumin-bound sirolimus for intravenous injection was approved by the FDA for the treatment of adults with locally advanced unresectable or metastatic malignant perivascular epithelioid cell tumour (PEComa). Sirolimus was also investigated in other cancers such as skin cancer, Kaposi’s Sarcoma, cutaneous T-cell lymphomas, and tuberous sclerosis. The topical formulation of sirolimus, marketed as HYFTOR, was approved by the FDA in April 2022: this marks the first topical treatment approved in the US for facial angiofibroma associated with tuberous sclerosis complex.