Table 1 Mitochondria-targeted chemotherapeutics (mitocans) as monotherapy against AML
From: Mitochondrial metabolism as a target for acute myeloid leukemia treatment
N | Drugs | Targets/inhibition related to mitochondria | AML subgroup if applicable | Level 1: preclinical (in vitro, PDX) | Level 2: clinical trials/studies in AML patients |
|---|---|---|---|---|---|
1. DNA-targeted agents/cytotoxic chemotherapy | |||||
 1.1.1 | Cytarabine | DNA polymerase, topoisomerase II, incorporation into DNA/RNA | AML | [165] | [166] |
 1.1.2 | Doxorubicin/idarubicin/daunorubicin | [167] | |||
 1.1.3 | Mitoxanthrone | [168] | [169] | ||
 1.1.4 | Etoposide | [170] | Phase II [171] | ||
 1.2 | ddC/alovudine | Mitochondrial DNA polymerase γ, OxPhos | AML | – | |
 1.3 | Bleomycin | mtDNA, OxPhos | AML | [174] | – |
2. Bcl-2 family inhibitors | |||||
 2.1.1 | Navitoclax | Bcl-2 | AML | [72] | – |
 2.1.2 | Obatoclax | [175] | – | ||
 2.1.3 | Venetoclax | R/R AML/unfit for intensive therapy | Phase II [138] | ||
 2.2 | Obatoclax | Pan Bcl-2 | de novo AML | [178] | Phase I/II [179] |
R/R AML | Phase I [180] | ||||
 2.3.1 | S63845/S64315 | Mcl1 | AML | [181] | Phase I (NCT02979366) |
 2.3.2 | A-1210477 | [182] | – | ||
 2.3.3 | AZD5991 | R/R AML | [183] | Phase I/II (NCT03218683) | |
 2.4 | α-TOS | Bid cleavage, complex I, ROS production | APL | – | |
3. Agents targeting mitochondrial metabolism | |||||
 3.1.1 | 2-DG | Hexokinase II | AML, FLT3-ITD AML | – | |
 3.1.2 | 3-BP | Hexokinase II, OxPhos, ROS production | – | ||
 3.1.3 | 3-BrOP | Hexokinase II | [43] | – | |
 3.2 | 3-PO | 6-Phosphofructo-1-kinase | AML | [37] | – |
 3.3.1 | CPI-613 | PDK, OxPhos | AML | [188] | Phase I [188] |
 3.3.2 | DAP | [189] | – | ||
 3.4 | Enasidenib | IDH2mut | IDH2mut R/R AML | [190] | Phase I/II [191] FDA-approved |
 3.5.1 | Telaglenastat | Glutaminase | AML | [192] | Phase I (NCT02071927) |
 3.5.2 | BPTES | AML with IDH1/2 mutations | [62] | – | |
 3.6.1 | ADI-PEG 20 | Arginine depletion | R/R or poor-risk AML | [193] | Phase II (NCT01910012) |
 3.6.2 | BCT-100 | Pediatric R/R AML | [194] | Phase I/II (NCT03455140) | |
 3.7 | L-asparaginase | Asparagine depletion, glutamine uptake inhibition | AML | [195] | Phase I (NCT02283190) |
 3.8.1 | Etomoxir | FAO (CPT1) | AML | [21] | – |
 3.8.2 | Ranolazine | FAO (3-ketoacyl CoA thiolase) | |||
 3.8.3 | ST1326 | FAO (CPT1) | [196] | ||
 3.8.4 | Avocatin B | FAO, ROS production, cytochrome c release | [197] | ||
4. Agents targeting OxPhos and/or mitochondrial biogenesis/respiration | |||||
 4.1 | Tigecycline | Mitochondrial translation, mitochondrial biogenesis | AML | [65] | Phase I [73] |
 4.2.1 | Metformin | Complex I, mitochondrial oxygen consumption | AML | [79] | – |
 4.2.2 | IACS-010759 | R/R AML | [81] | Phase I (NCT02882321) | |
 4.2.3 | Rotenone | AML | [35] | – | |
 4.3 | A2-32-01 | Mitochondrial protease ClpP, Complex II | AML | [90] | – |
 4.4 | Cysteinase | Complex II | AML | [198] | – |
 4.5 | Antimycin | Complex III | AML | [66] | – |
 4.6.1 | Isobavachalcone | Pyrimidine biosynthesis (DHODH) | AML | [199] | – |
 4.6.2 | PTC299 | R/R AML/AML patients unfit for standard therapy | [200] | Phase I (NCT03761069) | |
 4.6.3 | ASLAN003 | [201] | Phase II (NCT03451084) | ||
 4.6.4 | BAY 2402234 | AML | [202] | Phase I (NCT03404726) | |
5. Agents inducing ROS production/targeting MPTP | |||||
 5.1 | Arsenic trioxide | ANT, ROS production, MMP, DNA damage | De novo AML, secondary AML, R/R AML | [109] | Phase II [203] |
APL | Phase I/II (NCT00008697) | ||||
 5.2 | Lonidamine | ANT, OxPhos (complex II) | AML | – | |
 5.3 | Parthenolide | ROS production, NF-kB inhibition | AML | [206] | – |
 5.4 | Triptolide (minnelide as a soluble prodrug) | ROS production, Mcl1, MMP | AML | [207] | Phase I/Ib (NCT03760523) |
 5.5 | Resveratrol | NF-kB, apoptosis induction | AML | [208] | – |
6. Mitochondrial uncouplers | |||||
 6.1 | CCCP | MMP | AML | [67] | – |
 6.2 | Dichlorophenyl urea (SR4, SR9) | MMP | AML | [209] | – |