Table 3.
Summary of the drug development status for the activation of MiT members
| Compound | Mechanism of action | Disease / symptoms | Development stage | References / Clinical Trial |
|---|---|---|---|---|
| Rapamycin | Inhibitor of mTOR; autophagy activation; mitochondrial quality; control MiT activation | PD | Preclinical (in vitro and in vivo) | [186, 222] |
| Everolimus | Inhibitor of mTOR; immunosuppressant; inhibition of T-cell and B-cell proliferation | Immuno-suppression in heart transplant recipients | Clinical (pilot study) | [225] |
| Sirolimus and RTB101 (alone or in combination) | Inhibitors of mTOR; autophagy activation | PD; MSA | Clinical trial | anzctr.org.au (trial ID: ACTRN12619000372189), phase 1/2, trial information not updated; clinicaltrials.gov (trial ID: NCT03589976), phase 2, trial stopped |
| Dynasore | GTPase inhibitor targeting dynamin; TFE3 and TFEB activation | HD; PD | Preclinical (in vitro) | [227–229] |
| Trehalose | Naturally occurring sugar; TFEB activation | Tauopathy; PD | Preclinical (in vitro and in vivo) | [222, 230–232] |
| 2-Hydroxypropyl-β-cyclodextrin (HPβCD) | Drug delivery vehicle; TFEB activation | cholesterol storage disorder (NPC) | Preclinical (in vitro); clinical trial | [235, 236]; clinicaltrials.gov (trial ID: NCT03893071), phase 1/2; clinicaltrials.gov (trial ID: NCT03893071), phase 2/3 |
| Curcumin and its derivatives C1, C4 | mTOR-independent TFEB activators | AD; PD | Preclinical (in vitro and in vivo) | [237, 239–241] |
| Celecoxib | Cyclooxygenase 2 inhibitor; TFEB activation | PD | Preclinical (in vitro) | [243] |
| Ibudilast | Anti-inflammatory phosphodiesterase inhibitor; TFEB activation | Preclinical (in vitro) | [244] | |
| PP242 | mTORC1 inhibitor; TFEB activation | PD | Preclinical (in vitro) | [245] |
| Ambroxol | GCase chaperone; TFEB activation | PD | Preclinical (in vivo); clinical trial | [246, 248, 249]; clinicaltrials.gov (trial ID: NCT02941822), phase 2 completed; clinicaltrials.gov (trial ID: NCT02914366), phase 2 |
| Veliparib | PARP1 inhibitor; TFEB activation | PD | Preclinical (in vivo) | [220] |
| Trifluoperazine | Calmodulin and Dopamine receptor blockade; TFEB activation | PD | Preclinical (in vivo) | [210] |
Pharmacological compounds with a described direct or indirect action on the MiT pathway is provided. For each compound a proposed mechanism of action is listed, together with the disease for which the compound has been tested in connection with MiT pathway activation. The preclinical or clinical development stage of the drugs are shown with references describing the studies and relevant clinical trials