Overview of Research into mTOR Inhibitors

Abstract

The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that belongs to the phosphoinositide 3-kinase (PI3K)-related kinase (PIKK) family. The kinase exists in the forms of two complexes, mTORC1 and mTORC2, and it participates in cell growth, proliferation, metabolism, and survival. The kinase activity is closely related to the occurrence and development of multiple human diseases. Inhibitors of mTOR block critical pathways to produce antiviral, anti-inflammatory, antiproliferative and other effects, and they have been applied to research in cancer, inflammation, central nervous system diseases and viral infections. Existing mTOR inhibitors are commonly divided into mTOR allosteric inhibitors, ATP-competitive inhibitors and dual binding site inhibitors, according to their sites of action. In addition, there exist several dual-target mTOR inhibitors that target PI3K, histone deacetylases (HDAC) or ataxia telangiectasia mutated and Rad-3 related (ATR) kinases. This review focuses on the structure of mTOR protein and related signaling pathways as well as the structure and characteristics of various mTOR inhibitors. Non-rapalog allosteric inhibitors will open new directions for the development of new therapeutics specifically targeting mTORC1. The applications of ATP-competitive inhibitors in central nervous system diseases, viral infections and inflammation have laid the foundation for expanding the indications of mTOR inhibitors. Both dual-binding site inhibitors and dual-target inhibitors are beneficial in overcoming mTOR inhibitor resistance.

mTOR signaling regulates Zika virus replication bidirectionally through autophagy and protein translation

“…A previous study found that rapamycin‐induced autophagy but did not change viral protein expression or progeny production in ZIKV‐infected HUVECs. Rapamycin can occupy the catalytic site of mTOR to inhibit mTORC1 activity 11 . Rapamycin and its optimized derivatives, everolimus or temsirolimus, were utilized to determine whether the physical properties of rapamycin influenced ZIKV replication.…”

“…Rapamycin can occupy the catalytic site of mTOR to inhibit mTORC1 activity. 11 Rapamycin and its optimized derivatives, everolimus or temsirolimus, were utilized to determine whether the physical properties of rapamycin influenced ZIKV replication. The results indicated that they increased the intracellular viral RNA levels by approximately 2.5-fold but did not change viral protein NS1 expression or extracellular virus yields (Supporting Information: Figure S1), which suggested that rapamycin and its derivatives promote viral RNA transcription but not protein translation and excluded the influence of rapamycin's physical properties on ZIKV replication.…”

“…In addition, mTORC1 can interrupt the nuclear translocation of transcription factor EB (TFEB) to suppress autophagy 17 . mTORC2 mainly phosphorylates AKT at site S473 and activates PI3K/AKT signaling to regulate cell proliferation and survival 11 …”

Oral mTOR Inhibition Limits And Reduces Actinic Keratosis And Cutaneous Squamous Cell Carcinoma In A UVB-Induced Mouse Model

“…The HaCaT cell line is derived from adult trunk skin that was spontaneously immortalized and has UV-indicative p53 mutations found in both cSCC and normal human skin 32,33 . The three mTOR inhibitors selected for testing were vistusertib (AZD2014), omipalisib (GSK2126458), and CC-115, which are all dual mTORC1 and mTORC2 inhibitors [34][35][36][37] . In addition to targeting mTOR, omipalisib is a potent PI3K inhibitor, and CC-115 inhibits DNA-PK.…”

“…Of the three compounds, vistusertib exhibited the highest C max and AUC and omipalisib had the lowest values. Despite having lower overall serum concentrations, omipalisib has the lowest reported IC 50 for mTOR (~10 fold lower than vistusertib and ~70 fold lower than CC-115), thus its activity is likely to remain high at relatively low doses [34][35][36][37] . In a previously conducted experiment using the same animal model, we observed that vistusertib was well tolerated at a dose of 15 mg/kg and appeared to limit the development of keratoses (data not shown).…”