Table 1 Overview of existing/ongoing clinical developments.
From: Mitochondrial metabolism as a potential therapeutic target in myeloid leukaemia
Compounds | Mechanism of Action | Clinical Trial Results | References |
|---|---|---|---|
Venetoclax | Selectively inhibits BCL-2 protein | Phase 1b/2 trials of venetoclax plus a hypomethylating agent therapy showed tolerable and promising clinical activity, over 60 trials are currently ongoing | |
Biguanides | Inhibits the ETC complex I and the glycerol phosphate shuttle | Metformin trial in ALL relapsed patients showed a protective effect, however only high concentrations found effective in in vitro studies raising safety concerns for lactic acidosis, and phenformin trial in melanoma is currently in progress | |
Tigecycline | Inhibits the synthesis of mitochondrial ETC complex subunits encoded by mtDNA | Phase I trial on relapsed/refracted AML patients showed satisfactory safety profile, but unsuccessful clinical benefits of tigecycline | [150] |
IACS-010759 | Inhibits activity of ETC complex I | Satisfactory efficacy in in vivo AML and glioma models, however reported increased serum lactate levels and currently phase I trials on relapsed/refractory AML in progress | |
CPI-613 | Deactivates PDH and prevents the entry of acetyl-CoA into TCA cycle | Phase I trials undergone in relapsed/refractory AML patients with CPI-613 alone and in combination with cytarabine with promising results in the combination treatment, phase II trial currently ongoing | |
CB-839 | Inhibits glutaminolysis by targeting GLS | Pre-clinical data were positive and phase I trial in AML and phase II trial on advance myelodysplastic malignancies are currently ongoing | [155] |
Enasidenib | Inhibits the decarboxylation of isocitrate by inhibiting IDH2 | Phase I and II trials revealed enasidenib to be tolerable and to induce haematologic responses in relapsed/refractory mutant-IDH2 AML, phase III is ongoing | [13] |
