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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 [172, 173]
 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 [176, 177] 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 [184, 185]
3. Agents targeting mitochondrial metabolism
 3.1.1 2-DG Hexokinase II AML, FLT3-ITD AML [34, 43]
 3.1.2 3-BP Hexokinase II, OxPhos, ROS production [186, 187]
 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 [67, 204, 205]
 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]