MTOR inhibitors
Introduction
mTOR inhibitors are a class of drugs that inhibit the mechanistic target of rapamycin (mTOR), which is a serine/threonine-specific protein kinase that belongs to the family of phosphatidylinositol-3 kinase (PI3K) related kinases (PIKKs). These inhibitors have significant therapeutic potential in a variety of diseases, including cancer, cardiovascular disease, and autoimmune disorders.
Mechanism of Action
mTOR inhibitors work by binding to the mTOR complex and inhibiting its kinase activity. This prevents the phosphorylation of downstream targets, leading to a decrease in protein synthesis and cell proliferation. The mTOR pathway is a central regulator of cell growth and proliferation, and its dysregulation is implicated in a variety of diseases.
Types of mTOR Inhibitors
There are two main types of mTOR inhibitors: rapalogues and ATP-competitive inhibitors.
Rapalogues
Rapalogues, such as rapamycin and its analogues (temsirolimus, everolimus, and ridaforolimus), bind to the intracellular protein FKBP12. The resulting complex then binds to mTOR complex 1 (mTORC1), inhibiting its activity.
ATP-Competitive Inhibitors
ATP-competitive inhibitors, such as AZD8055 and PP242, bind directly to the ATP-binding site of mTOR. These inhibitors are more potent and selective than rapalogues, and they inhibit both mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2).
Clinical Applications
mTOR inhibitors have a wide range of clinical applications due to their ability to regulate cell growth and proliferation.
Cancer
In cancer, mTOR inhibitors are used to block the growth and proliferation of tumor cells. They are currently approved for the treatment of certain types of kidney, breast, and pancreatic cancers.
Cardiovascular Disease
In cardiovascular disease, mTOR inhibitors are used to prevent restenosis, which is the re-narrowing of blood vessels after they have been widened by angioplasty.
Autoimmune Disorders
In autoimmune disorders, mTOR inhibitors are used to suppress the immune system and prevent it from attacking the body's own tissues.
Side Effects
Like all drugs, mTOR inhibitors can have side effects. These can include mouth sores, infections, fatigue, diarrhea, and rash. In some cases, they can also cause more serious side effects like lung or breathing problems, kidney failure, or high blood sugar.
Future Directions
Research is ongoing to develop new mTOR inhibitors and to find new uses for existing ones. This includes investigating their potential use in neurodegenerative diseases, diabetes, and aging.