5.3. Therapeutic agents targeting the MTORC1 pathway
Regarding the role of MTORC1 in mitophagy and the effect of melatonin on MTORC1 regulation, it can be assumed that inhibiting MTORC1 may upregulate mitophagy. Besides, a combinational therapeutic system including melatonin and MTORC1 inhibitors might show satisfactory results.
Rapamycin is an FDA-approved MTORC1 inhibitor employed in clinics for suppression of organ rejection following tissue transplantation and cancer treatment (Kennedy & Lamming, 2016). In various disease models, rapamycin protects mitochondria via enhancing mitophagy (Li et al., 2018; Li et al., 2014). Of note, melatonin reduces transplant rejection probably due to its antioxidant property to reduce rapamycin toxicity, denoting the value of combining melatonin with rapamycin (Vairetti et al., 2005). A derivative of rapamycin, Everolimus serves as an immunosuppressant, now in phase II of clinical trials. Everolimus has been shown to block MTORC1 with greater specificity (Goutagny et al., 2015). Also, temsirolimus is a preclinical therapeutic agent with the potential to inhibit MTORC1 through allosteric regulation, leading to mitophagy activation (Chiarini et al., 2011). Ridaforolimus/deforolimus is another novel MTORC1 inhibitor which went through several phases I/II and even phase III clinical trials for the treatment of certain tumors (Mita, Sankhala, Abdel-Karim, Mita & Giles, 2008).