Sirolimus [BSA]

As an antifungal agent, rapamycin (also known as sirolimus) is known for its immunosuppressive and antiproliferative properties in mammalian cells, where it is a potent inhibitor of S6K1 (serine/threonine kinase) activation and a mediator of phosphatidylinositol 3-kinase (PI3K). Rapamycin forms a gain-of-function complex with FK506 binding protein (FKBP12), binds to the mechanistic target of rapamycin (mTOR) complex 1 (mTORC1), and acts as a specific heterodimeric inhibitor. mTORC1 inhibits eukaryotic translation initiation factor 4E (eIF4E)-binding protein 1 (4EBP1) and activates S6K, which activates protein synthesis, ribosome biogenesis, nutrient transport, and lipid synthesis in response to nutrients, growth factors and cellular energy. The mTOR complex 2 also contains mTORs. mTORC1 is sensitive to acute administration of rapamycin, and mTORC2 is associated with long-term exposure to rapamycin. Sirolimus is a first-generation mTOR inhibitor that acts at a later stage of T lymphocyte activation and is an alternative to cytokine-driven inhibitors of lymphocyte proliferation.

Figure 1. Pathways involved in inhibition of mTOR
(Source: Nguyen LS, et al. 2019)

Gain-of-function or loss-of-function mutations in oncogenes are associated with increased mTORC1 activation, which drives protein synthesis. At the same time, oncogenic activation of mTORC1 promotes gene expression programs and thus participates in metabolic reprogramming of cancer cells. In addition, mTORC1 activation promotes glycolysis, lipid biosynthesis and the pentose phosphate pathway, and positively regulates glutamine metabolism by inhibiting SIRT4. Targeting mTORC1 with rapamycin inhibits tumor metabolism and is considered a promising anticancer therapy. Rapamycin is also used to treat lymphangioleiomyomatosis (LAM) and tuberous sclerosis (TSC), both of which are caused by loss-of-function mutations in the TSC gene, the protein product of which acts as a complex to inhibit mTORC1 activity. Several clinical trials investigating the efficacy of rapamycin-based therapy have shown that continued administration of the drug stabilizes lung function and improves quality of life, but that lung function deteriorates when the drug is discontinued. However, since rapamycin suppresses immune function and may lead to serious side effects, the safety of long-term use needs to be further verified.

Rapamycin