Overview

Sirolimus (commonly referred to as “rapamycin” in basic research papers) is a macrolide compound with antifungal properties, isolated from the soil bacteria found on Easter Island (“Rapa Nui” in the local language).
Sirolimus is widely used as an immunosuppressant following kidney transplants and is also used as a coating agent for coronary stents to prevent restenosis.
Sirolimus has been approved as a treatment for lymphangioleiomyomatosis (LAM). The rapalog (i.e., rapamycin derivative) Everolimus has been approved as a treatment for tuberous sclerosis complex.

Rapamycin forms a complex with the protein FKBP12 and binds to the serine/threonine kinase known as mTOR (mammalian or mechanical target of rapamycin) to inhibit its activity. It is thought to be a promising compound for treating diseases caused by the excessive activation of mTOR.

mTOR is a kinase that regulates cell growth, promoting cell proliferation and increased cell volume. Cells grow and proliferate through activation by nutrients (amino acids) and growth factors, the promotion of protein synthesis, the suppression of proteolysis (autophagy), and the regulation of lipid and sugar metabolism, as shown in the figure below.

The abnormal activation of this pathway can result in a number of diseases, including tuberous sclerosis complex. This disease is caused by loss-of-function mutation in the causative genes TSC1 and TSC2, complexes that suppress the activity of mTOR (see figure). In tuberous sclerosis complex, mTOR is activated by the failure of this suppression, resulting in tumors in numerous organs.

In LAM as well, mutations in the TSC genes cause the excessive activation of mTOR and the proliferation of smooth muscle-like cells. Sirolimus and its derivatives act to suppress abnormal cell proliferation by suppressing the activation of mTOR. Similarly, sirolimus-eluting stents act to suppress restenosis caused by the proliferation of vascular smooth muscle.

Tuberous sclerosis complex is a hereditary disorder, but somatic cell mutations in mTOR or mTOR signaling molecules (as shown in the figure) have been reported in many tumors and in focal cortical dysplasia (FCD) and hemimegalencephaly. Activating mutations of mTOR itself have been found in tumors and in FCD. Sirolimus is expected to demonstrate an effectiveness in treating these as well.