Table 1.

Compounds FDA approved or under preclinical and clinical development that target AML metabolism

Serial numberDrugs/compoundsEnzymes/metabolic pathways affected and its mechanismIn vitro/preclinical/clinical trialsReferences
Amino acid metabolism and therapeutic drugs     
1 Gabapentin BCAT1 inhibitor/BCAA depletion; accumulation of αKG and impaired leukemogenesis. In vitro 15  
2 SETD2-IN-1 TFA SETD2 inhibitor; preventing the transfer of methyl groups from SAM to H3K36 by SETD2. Preclinical 16  
3 SAHH inhibitor SAHH inhibitor; preventing the conversion of SAH to homocysteine, thereby altering the SAM:SAH ratio and disrupting the SAM cycle. Preclinical 16  
4 Indoximod (1MT), epacadostat (INCB024360), and linrodostat (BMS986205) IDO inhibitors; activating immune system (T cells and natural killer cells). Preclinical/phase 1 17, 18  
5 CB-839, BPTES GLS inhibitor/glutamine depletion; decreased OXPHOS, reduced GSH, and increased ROS. Preclinical 19  
6 ASNase + Ara-C Depletion of circulating asparagine. Phase 1/2 20  
7 BCT-100, ADI-PEG20 Depletion of extracellular and intracellular arginine concentrations. Preclinical 21, 22  
8 Cyst(e)inase Depletion of cysteine; reduced extracellular L-cysteine, depleted intracellular GSH, enhanced intracellular ROS, induced cell cycle arrest, and apoptosis. Preclinical 23  
9 Parthenolide Depletion of GSH in cysteine metabolism; depleted GSH and inhibited GSH metabolic enzymes (eg, GCLC and GPX1), and induced oxidative stress. In vitro 24  
10 WQ-2101 + Ara-C Inhibition of PHGDH. Preclinical 25  
11 RZ-2994, SHIN-2 Inhibition of SHMT1 and SHMT2. Preclinical 26, 27  
FA metabolism and therapeutic drugs     
12 Dehydrocurvularin ATP citrate lyase inhibition. Preclinical 28  
13 Bezafibrate + medroxyprogesteron acetate Prostaglandin inhibition. In vitro 29, 30  
14 Statin-dipyridamole HMG-CoA reductase inhibitor/MVA biosynthesis inhibition. Preclinical 31  
15 Statin + (venetoclax or navitoclax) MVA biosynthesis inhibition, BCL-2 and BCL-XL inhibitor, and upregulation of the p53 protein. In vitro 32  
16 Statin MVA biosynthesis inhibition; upregulation of the p53 protein and isoprenylation of the Rho and Ras GTPases. Phase 2 33  
17 LCL204 Ceramide inhibition. Preclinical 34  
Nucleotide metabolism and therapeutic drugs     
18 6-thioguanine PRPP amidotransferase inhibitor. Clinical trials 35  
19 FF-10501 IMPDH inhibitor/inhibit purine metabolism. Phase 1 (#NCT02193958) 36, 37  
20 Ara-C, gemcitabine Pyrimidine analog/inhibit nucleotide biosynthesis. FDA approved 38  
21 BAY-2402234
ASLAN003
PTC299 		Dihydrofolate dehydrogenase inhibition. Phase 1 (#NCT03404726)
Phase 2 (#NCT03451084)
Phase 3 (#NCT03761069) 		39, 40, 41  
22 5-fluoro-2′-deoxyuridine-5′-O-monophosphate[10] Thymidylate synthetase (TS) inhibitor/reduce thymidine nucleotide. Preclinical 42  
Glycolytic and mitochondrial OXPHOS and therapeutic drugs     
23 2,5-anhydro-D-mannitol + Ara-C Fructose analog/inhibit GLUT5. Preclinical 43  
24 2-DG HK/glycolytic pathway; compete with glucose and phosphorylated into 2-DG-6-P. Preclinical 44, 45, 46  
25 3-PO PFKFB3 inhibitor/glycolytic pathway; suppressed glucose uptake and decreased intracellular lactate levels. Preclinical 47  
26 TT-232 PKM2 inhibitor/glycolytic pathway; induced apoptosis and promoted autophagy. Preclinical 48  
27 CPI-613 (devimistat) PDH and αKG-dehydrogenase complexes inhibition/TCA cycle. Phase 3 (#NCT03504410) 49  
28 2,2-dichloroacetophenone Inhibits PDK1, increased the activation of proapoptotic protein (PARP and caspase 3), decreased the expression of antiapoptotic protein (BCL-XL, BCL-2). Preclinical 50  
29 Ivosidenib (AG-120)
Enasidenib (AG221) 		IDH1 inhibitor; reduce 2-HG
IDH2 inhibitor and 2-HG synthesis. 		FDA approved 6, 7, 51  
30 ABT-737, ABT-264 OXPHOS inhibition. In vitro 52  
31 Venetoclax + azacitidine TCA cycle and OXPHOS inhibition. FDA approved 11, 53  
32 2′3′-dideoxycytidine mtDNA polymerase γ inhibition, inhibition of mtDNA replication and OXPHOS. Preclinical 54, 55  
33 2-C-methyladenosine Inhibition of OXPHOS and termination of mitochondrial transcription. Preclinical 56  
Vitamins and therapeutic drugs     
34 Vitamin C Cofactor of Fe2+ and αKG-dependent dioxygenases, promotes TET2 activity to limit HSPC self-renewal and leukemogenesis. Clinical trials (#NCT03526666 and #NCT02877277) 57, 58, 59  
35 Isoniazid, 4′-O-methoxypyridoxine Inhibition of PLP/pyridoxal kinase activity. Preclinical 60  
36 ATRA + arsenic trioxide Overcome the differentiation arrest through transcriptional de-repression and degradation of PML-RARA. Phase 3 (#NCT00482833) 61  
Resistance mechanisms to the current treatment     
37 Venetoclax + azacitidine + tedizolid Inhibition of mitochondrial translation. Preclinical 62  
38 Venetoclax + ibrutinib
Venetoclax + cobimtinib 		OXPHOS and Bruton tyrosine kinase inhibition.
OXPHOS and MEK inhibition. 		Preclinical 63, 64  
Serial numberDrugs/compoundsEnzymes/metabolic pathways affected and its mechanismIn vitro/preclinical/clinical trialsReferences
Amino acid metabolism and therapeutic drugs     
1 Gabapentin BCAT1 inhibitor/BCAA depletion; accumulation of αKG and impaired leukemogenesis. In vitro 15  
2 SETD2-IN-1 TFA SETD2 inhibitor; preventing the transfer of methyl groups from SAM to H3K36 by SETD2. Preclinical 16  
3 SAHH inhibitor SAHH inhibitor; preventing the conversion of SAH to homocysteine, thereby altering the SAM:SAH ratio and disrupting the SAM cycle. Preclinical 16  
4 Indoximod (1MT), epacadostat (INCB024360), and linrodostat (BMS986205) IDO inhibitors; activating immune system (T cells and natural killer cells). Preclinical/phase 1 17, 18  
5 CB-839, BPTES GLS inhibitor/glutamine depletion; decreased OXPHOS, reduced GSH, and increased ROS. Preclinical 19  
6 ASNase + Ara-C Depletion of circulating asparagine. Phase 1/2 20  
7 BCT-100, ADI-PEG20 Depletion of extracellular and intracellular arginine concentrations. Preclinical 21, 22  
8 Cyst(e)inase Depletion of cysteine; reduced extracellular L-cysteine, depleted intracellular GSH, enhanced intracellular ROS, induced cell cycle arrest, and apoptosis. Preclinical 23  
9 Parthenolide Depletion of GSH in cysteine metabolism; depleted GSH and inhibited GSH metabolic enzymes (eg, GCLC and GPX1), and induced oxidative stress. In vitro 24  
10 WQ-2101 + Ara-C Inhibition of PHGDH. Preclinical 25  
11 RZ-2994, SHIN-2 Inhibition of SHMT1 and SHMT2. Preclinical 26, 27  
FA metabolism and therapeutic drugs     
12 Dehydrocurvularin ATP citrate lyase inhibition. Preclinical 28  
13 Bezafibrate + medroxyprogesteron acetate Prostaglandin inhibition. In vitro 29, 30  
14 Statin-dipyridamole HMG-CoA reductase inhibitor/MVA biosynthesis inhibition. Preclinical 31  
15 Statin + (venetoclax or navitoclax) MVA biosynthesis inhibition, BCL-2 and BCL-XL inhibitor, and upregulation of the p53 protein. In vitro 32  
16 Statin MVA biosynthesis inhibition; upregulation of the p53 protein and isoprenylation of the Rho and Ras GTPases. Phase 2 33  
17 LCL204 Ceramide inhibition. Preclinical 34  
Nucleotide metabolism and therapeutic drugs     
18 6-thioguanine PRPP amidotransferase inhibitor. Clinical trials 35  
19 FF-10501 IMPDH inhibitor/inhibit purine metabolism. Phase 1 (#NCT02193958) 36, 37  
20 Ara-C, gemcitabine Pyrimidine analog/inhibit nucleotide biosynthesis. FDA approved 38  
21 BAY-2402234
ASLAN003
PTC299 		Dihydrofolate dehydrogenase inhibition. Phase 1 (#NCT03404726)
Phase 2 (#NCT03451084)
Phase 3 (#NCT03761069) 		39, 40, 41  
22 5-fluoro-2′-deoxyuridine-5′-O-monophosphate[10] Thymidylate synthetase (TS) inhibitor/reduce thymidine nucleotide. Preclinical 42  
Glycolytic and mitochondrial OXPHOS and therapeutic drugs     
23 2,5-anhydro-D-mannitol + Ara-C Fructose analog/inhibit GLUT5. Preclinical 43  
24 2-DG HK/glycolytic pathway; compete with glucose and phosphorylated into 2-DG-6-P. Preclinical 44, 45, 46  
25 3-PO PFKFB3 inhibitor/glycolytic pathway; suppressed glucose uptake and decreased intracellular lactate levels. Preclinical 47  
26 TT-232 PKM2 inhibitor/glycolytic pathway; induced apoptosis and promoted autophagy. Preclinical 48  
27 CPI-613 (devimistat) PDH and αKG-dehydrogenase complexes inhibition/TCA cycle. Phase 3 (#NCT03504410) 49  
28 2,2-dichloroacetophenone Inhibits PDK1, increased the activation of proapoptotic protein (PARP and caspase 3), decreased the expression of antiapoptotic protein (BCL-XL, BCL-2). Preclinical 50  
29 Ivosidenib (AG-120)
Enasidenib (AG221) 		IDH1 inhibitor; reduce 2-HG
IDH2 inhibitor and 2-HG synthesis. 		FDA approved 6, 7, 51  
30 ABT-737, ABT-264 OXPHOS inhibition. In vitro 52  
31 Venetoclax + azacitidine TCA cycle and OXPHOS inhibition. FDA approved 11, 53  
32 2′3′-dideoxycytidine mtDNA polymerase γ inhibition, inhibition of mtDNA replication and OXPHOS. Preclinical 54, 55  
33 2-C-methyladenosine Inhibition of OXPHOS and termination of mitochondrial transcription. Preclinical 56  
Vitamins and therapeutic drugs     
34 Vitamin C Cofactor of Fe2+ and αKG-dependent dioxygenases, promotes TET2 activity to limit HSPC self-renewal and leukemogenesis. Clinical trials (#NCT03526666 and #NCT02877277) 57, 58, 59  
35 Isoniazid, 4′-O-methoxypyridoxine Inhibition of PLP/pyridoxal kinase activity. Preclinical 60  
36 ATRA + arsenic trioxide Overcome the differentiation arrest through transcriptional de-repression and degradation of PML-RARA. Phase 3 (#NCT00482833) 61  
Resistance mechanisms to the current treatment     
37 Venetoclax + azacitidine + tedizolid Inhibition of mitochondrial translation. Preclinical 62  
38 Venetoclax + ibrutinib
Venetoclax + cobimtinib 		OXPHOS and Bruton tyrosine kinase inhibition.
OXPHOS and MEK inhibition. 		Preclinical 63, 64  

FDA, Food and Drug Administration; SAHH, S-adenosylhomocysteine hydrolase.

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