What are mechanistic target of rapamycin (mTOR) inhibitors?

From the Guidelines

mTOR inhibitors are a class of medications that include everolimus, with a recommended starting dose of 5mg in adults and 2.5mg/m2 in children with tuberous sclerosis complex, as suggested by recent clinical practice recommendations 1. These drugs work by inhibiting the mechanistic target of rapamycin complex 1 (mTORC1) pathway, which regulates cell growth, proliferation, and metabolism. Key points to consider when using mTOR inhibitors include:

• Dosing schemes may require individualized adaptation, such as intermittent treatment 1
• Dose adjustment is recommended in cases of mild adverse events before discontinuing treatment 1
• Everolimus trough levels should be obtained where safety concerns arise, adherence problems are suspected, or lack of efficacy is observed 1
• Target trough levels of everolimus should not exceed 15ng/ml 1 mTOR inhibitors have various applications, including transplant medicine, cancer treatment, and rare diseases like tuberous sclerosis complex. Regular monitoring of drug levels and potential complications is necessary, and patients should be aware of potential side effects and interactions with other medications, such as grapefruit and St. John's wort. The use of mTOR inhibitors should be guided by the most recent and highest-quality evidence, with a focus on minimizing morbidity, mortality, and improving quality of life 1.

From the FDA Drug Label

Everolimus is an inhibitor of mammalian target of rapamycin (mTOR), a serine-threonine kinase, downstream of the PI3K/AKT pathway. The mTOR pathway is dysregulated in several human cancers and in tuberous sclerosis complex (TSC) Everolimus binds to an intracellular protein, FKBP-12, resulting in an inhibitory complex formation with mTOR complex 1 (mTORC1) and thus inhibition of mTOR kinase activity.

mTOR inhibitors are drugs that inhibit the activity of the mammalian target of rapamycin (mTOR), a serine-threonine kinase involved in cell growth and proliferation.

• They work by binding to an intracellular protein, resulting in the formation of an inhibitory complex with mTOR complex 1 (mTORC1), which inhibits mTOR kinase activity.
• Examples of mTOR inhibitors include everolimus 2.
• mTOR inhibitors have been shown to reduce cell proliferation, angiogenesis, and glucose uptake in in vitro and/or in vivo studies.

From the Research

Definition and Function of mTOR Inhibitors

• mTOR (mechanistic target of rapamycin) inhibitors are macrocyclic lactone antibiotics derived from Streptomyces hygroscopicus that prevent T lymphocyte activation and B cell differentiation 3.
• They block the cytokine signal transduction to arrest cells in the G1 to S phase, and are commonly used for post-transplantation and cancer management due to their immunosuppressive and antiproliferative properties 3.
• mTOR inhibitors are also known as proliferation signal inhibitors (PSIs) because of their effects on proliferation pathways 3.

Types and Examples of mTOR Inhibitors

• Examples of mTOR inhibitors include sirolimus (rapamycin), everolimus, and temsirolimus, which are approved by the FDA for various indications such as post-renal transplantation, lymphangioleiomyomatosis (LAM), and advanced renal cell carcinoma (RCC) 3.
• mTOR inhibitors can be classified into four categories: antibiotic allosteric mTOR inhibitors, ATP-competitive mTOR inhibitors, mTOR/PI3K dual inhibitors, and other new mTOR inhibitors 4.

Mechanism of Action and Effects

• mTOR inhibitors block the mTOR signaling pathway, producing anti-inflammatory, anti-proliferative, autophagy, and apoptosis induction effects 4.
• They can affect various downstream pathways regulated by mTOR, making them potential therapeutic agents for managing different diseases 3, 5.
• The cellular and molecular effects of mTOR inhibitors, such as everolimus, have been studied in cancer therapy, and have shown promise in attenuating cell growth of cancer cells 6.

Clinical Applications and Research

• mTOR inhibitors are being researched for their potential use in other transplantation, metabolic disease, and cancer management 3, 5.
• Clinical trials are ongoing to explore the efficacy and safety of mTOR inhibitors in various indications, including cancer and kidney diseases 5, 7.
• The structure-activity relationship of mTOR inhibitors has been analyzed, and new scaffolds have been proposed for the design of future mTOR inhibitors 4.