Recent advances in targeting mTOR signaling pathway using small molecule inhibitors

Abstract

Targeted-based cancer therapy (TBCT) or personalized medicine is one of the main treatment modalities for cancer that has been developed to decrease the undesirable effects of chemotherapy. Targeted therapy inhibits the growth of tumor cells by interrupting with particular molecules required for tumorigenesis and proliferation of tumor cells rather than interfering with dividing normal cells. Therefore, targeted therapies are anticipated to be more efficient than former tumor treatment agents with minimal side effects on non-tumor cells. Small molecule inhibitors (SMIs) are currently one of the most investigated anti-tumor agents of TBCT. These small organic agents target several vital molecules involved in cell biological processes and induce target cells apoptosis and necrosis. Mechanistic (mammalian) target of rapamycin (mTOR) complexes (mTORC1/2) control different intracellular processes, including growth, proliferation, angiogenesis and metabolism. Signaling pathways, in which mTOR complexes are involved in are usually dysregulated in various tumors and have been shown to be ideal targets for SMIs. Currently, different mTOR-SMIs are in the clinic for the treatment of cancer patients, and several others are in preclinical or clinical settings. In this review, we summarize recent advances in developing different mTOR inhibitors, which are currently in preclinical and clinical investigations or have been approved for cancer treatment.

Strategies to Inhibit Myc and Their Clinical Applicability

“…While inhibition of mTOR alone in a mouse model of colorectal tumorigenesis failed to inhibit translation of myc , a small molecule inhibitor of eIF4A, silvestrol, effectively reduced myc translation, inhibiting tumor growth (Wiegering et al, 2015 ). Multiple mTOR and mTORC1/2 kinase inhibitors are currently approved for clinical use, and there is a significant focus on targeting many members of these signaling pathways (Polivka and Janku, 2014 ; Roohi and Hojjat-Farsangi, 2016 ).…”

Investigating the effect of target of rapamycin kinase inhibition on the Chlamydomonas reinhardtii phosphoproteome: from known homologs to new targets

“…Torin1 has slower off‐binding kinetics than other mTOR inhibitors in mammalian cell lines, possibly due to conformational change induction in the kinase that is energetically more difficult to recover from leading to a more pronounced and longer inhibition of the TORC1 pathway (Liu et al ., ). AZD8055 is an ATP‐competitive inhibitor of mTOR and all PI3K class I isoforms noted to inhibit the mTORC1 and mTORC2 substrate phosphorylation (Roohi & Hojjat‐Farsangi, ). These drugs were used to inhibit TOR activity in plants where rapamycin treatment is not highly effective (Zhang et al ., ; Montane & Menand, ).…”

The role of mTOR signaling pathway on cognitive functions in cerebral ischemia-reperfusion

“…Moreover, in rats with appropriate treatment after cerebral ischemia-reperfusion, there was no significant difference in the expression of mTOR signaling pathway related genes in hippocampus when compared with healthy rats (P>0.05), and its cognitive function was not significantly decreased, suggesting the decline of cognitive function in rats after cerebral ischemia-reperfusion may be generated through the mTOR signaling pathway. Further studies on the mTOR signaling pathway have found that the mTOR signaling pathway participates in many physiological and biochemical reactions in cells ( 22 , 23 ). For example, previous results have shown that the mTOR signaling pathway can sense the changes of intracellular energy as well as intracellular nutrients, thus regulating many physiological reactions in cells including gene transcription, translation, ribosome generation and amino acid intake.…”

“…For example, previous results have shown that the mTOR signaling pathway can sense the changes of intracellular energy as well as intracellular nutrients, thus regulating many physiological reactions in cells including gene transcription, translation, ribosome generation and amino acid intake. Furthermore, the mTOR signaling pathway plays an important role in the regulation of multiple neural processes, such as formation and development of the brain, formation and maturation of synapses and neural cell proliferation ( 22 , 23 ).…”