Table 1.
Drugs targeting amino acid metabolism in myeloid malignancies.
| Amino acid | Drug(s) | Target | Disease type or model | Response | Reference |
|---|---|---|---|---|---|
| Methionine | PF-9366 | MAT2 | AML bearing MLL-AF9 fusion protein | Reduction in cell viability | (9, 10) |
| AEP, AMB, Cycloleucine | MAT1, MAT2, MAT3 | Untested in myeloid Malignancies | N/A | (11–13) | |
| Pinometostat | SAM | AML blast from adult and pediatric patients | Reduction in H3K9me | (14) | |
| GSK-343 | SAM | AML cell line Kasumi | Reduction in H3K27me3, G0/G1 cell cycle arrest | (15) | |
| LLY-283 | SAM | AML cell lines MOLM-13 and MV411 | Blocks cell proliferation in vitro | (16) | |
| PEG-rMETase | Extracellular methionine depletion | Untested in myeloid malignancies | N/A | (24) | |
| Cysteine | AOAA | CBS | CML cell line K562 | Inhibition of proliferation and induction of apoptosis in vitro | (21) |
| BCAAs | ERG240 | BCAT1 | Myeloid cells | Reduces oxygen consumption, glycolysis and itaconate levels | (30, 31) |
| BCH | LAT1, LAT2, LAT3 | AML cell lines HL60 and NB40; CML cell line K562 | Reduces growth rate in vitro; downregulates S6RP phosphorylation. | (39, 40) | |
| JPH203, SKN103 | LAT1 | Untested in myeloid malignancies | N/A | (38, 41) | |
| Tryptophan | Indoximod | IDO | Patient derived AML blast. | Reversed blast-mediated suppressive effect on T cell proliferation in vitro | (44) |
| Newly diagnosed AML patients | Ongoing phase I/II trial (NCT02835729) in combination with Cytarabine | N/A | |||
| Epacadostat | IDO | Patients with advanced MDS after Azacytidine treatment | Stable disease in 80% of cases. Marginal reduction in MDSCs and Tregs | (58) | |
| Navoximod | IDO | Co-culture experiments with human monocytes derived dendritic cells and T cells | Restores T-cell proliferation in vitro | (59) | |
| Lirondostat | IDO | Patients with MDS or AML | Ongoing Phase I/II trial (NCT02835634) in combination with Nivolumab | N/A | |
| Glutamine | CB839 | GLS | Patient derived AML blasts | Reduces intracellular glutamate titers with corresponding reduction in cell viability | (63–65) |
| Patients with advanced MDS after Azacytidine treatment | 70% complete response. Sensitivity is increased when administered in conjunction with the FLT3 inhibitor AC220 | (66, 68) | |||
| V9302 | ASCT2 | Blasts isolated from bone marrow of transgenic mouse model of MLL-AF9 induced AML | V9302 leads to reduction in glutamine and leucine uptake, inhibition of mTOR and induction of cell death. | (69) | |
| Cysteine | Erastin | xCT | AML cell lines | Increased intracellular ROS production and cell death by ferroptosis | (72, 73) |
| Serine, Glycine | WQ2101 | PHGHD | AML cell lines MV411, MOLM13, PL21 | Induction of apoptosis only in cells harboring FLT3-ITD mutations | (77). |
| PHGHD-Hit, BI4924, NCT502, NCT502 | PHGHD | Untested in myeloid malignancies | N/A | (78, 79) | |
| Pemetrexed, Lometrexol, Methotrexate, Raltitrexed | SHMT2 | Recombinant human SHMT2 | Up to 60% reduction in SHMT2 activity | (83) | |
| Compound 12.2 | SHMT2 | CML Cell line HAP1 | Reduction in cell viability | (82) | |
| AGF291, AGF30, AGF347 | SHMT2 | Untested in myeloid malignancies | N/A | (84) | |
| Arginine | CB1158 | Arg1, Arg2 | Myeloid cells | Blocks myeloid cell mediated inhibition of T-cell and NK cell proliferation | (89) |
| BCT-100 | Extracellular arginine depletion | Primary AML blast for adult and pediatric patients | Induction of G0/G1 cell cycle arrest, shortly followed by necrotic cell death | (85) | |
| ADI-PEG | ASS-1 negative AML patient derived xenograft | Reduced AML burden in tumor bearing mice | (105) | ||
| Ornithine | DFMO | ODC | Five AML patients treated in combination with MGBG | Complete response in one patient and partial response in four | (100) |
| AML cell line THP1 | Induction of cell death characterized by cleavage of PARP, Caspase 3 and Caspase 7 | (101) | |||
| CML Cell line K562 or myeloid cells | Decreased Polyamine synthesis and reduction in proliferation | (102) | |||
| AO476 | AMD1 | Patient derived CML blasts | Activated the integrated stress response and led to a reduction in proliferation | (98) | |
| Asparagine | ASNase | Extracellular asparagine and glutamine depletion | Patient derived AML blasts | Increased toxicity in FAB, M5, M1 and M4 AML subtypes and resistance in M3 and M2 (determined by MTT assays) | (109) |
| AML cell line U937; primary AML blasts | Induction of apoptosis in vitro and increase survival in U937 xenograft mice | (60, 111) | |||
| Five adult AML patients | Reduction in plasma glutamine and asparagine in all five patients; complete response in two patients, partial response in one | (112) | |||
| Leukemic stem cells | Induction of apoptosis; reduced cytotoxicity when co-cultured with mesenchymal stem cells or macrophages | (113) |