Table 1.
Cancer therapies/drugs that target metabolic pathways. Key targets of nucleoside analogs are shown; however, most nucleoside analogs inhibit multiple nucleic acid and DNA synthesis/repair enzymes including DNA polymerase.
| Metabolic Pathway | Target | Drug | Stage of Development | References |
|---|---|---|---|---|
| Nucleic acid synthesis | Thymidylate synthase (TS) | 5-fluorouracil Capecitabine Pemetrexed Raltitrexed |
Approved | [162–165] |
| Dihydrofolate reductase (DHFR) | Methotrexate Pemetrexed |
Approved | [164, 166, 167] | |
| Glycinamide ribonucleotide formyltransferase (GARFT) | Pemetrexed |
Approved | [164] | |
| dihydroorotate dehydrogenase (DHODH) | Brequinar Leflunomide |
Phase I/II | [168] | |
| Ribonucleotide reductase (RNR) | Gemcitabine Clofarabine Fludarabine Cladribine Cytarabine |
Approved | [169–173] | |
| 5-phosphoribosyl-1-pyro-phosphatase (PRPP) amidotransferase | Mercaptopurine Thioguanine |
Approved | [174–176] | |
| Glycolysis | GLUT1 | WZB117 BAY-876 |
Pre-clinical | [116, 177] |
| Hexokinase | 2-deoxyglucose |
Phase I/II | [106] | |
| Pyruvate Kinase M2 (PKM2) | TEPP-46 | Pre-clinical | [111] | |
| Lactate dehydrogenase A (LDHA) | Quinoline 3-sulfonamides FX11 PSTMB |
Pre-clinical | [117, 178, 179] | |
| Monocarboxylate transporter 1 (MCT1) | AZD3965 | Phase I | [119] | |
| Glutamine metabolism | Glutaminase 1 (GLS1) | CB-839 IPN60090 |
Phase I/II | [123, 124, 126] |
| ASCT2 (SLC1A5) | GPNA | Pre-clinical | [128, 180] | |
| multiple targets | JHU-083 | Pre-clinical | [93, 181] | |
| Amino acid transport and biosynthesis | Phosphoglycerate dehydrogenase (PHGDH) | CBR-5884 NCT-503 |
Pre-clinical | [131–133] |
| Indoleamine-2,3-dioxygenase-1 (IDO1) | Epacadostat Indoximod |
Phase III | [137] | |
| Circulating asparagine | L-Asparaginase | Approved | [105] | |
| Large neutral amino acid transporter (LAT1) | JPH203 | Pre-clinical | [129, 182] | |
| Mitochondrial metabolism | Pyruvate dehydrogenase (PDH), α-ketoglutarate dehydrogenase | CPI-613 | Phase II | [183] |
| Electron Transport Chain Complex 1 | Metformin IACS-010759 |
Phase I-III | [184, 185] | |
| Lipid metabolism | ATP-citrate lyase (ACLY) | SB-204990 | Pre-clinical | [142, 143] |
| acetyl-CoA carboxylase (ACC) | Soraphen-A | Pre-clinical | [144, 145] | |
| fatty acid synthase (FASN) | TVB-2640 | Phase II | [141] | |
| Enzymes mutated in cancer | Mutant isocitrate dehydrogenase 1 (IDH1) | AG-120 BAY1436032 LY3410738 FT-2102 |
Phase I-III | [156, 157] |
| Mutant isocitrate dehydrogenase 2 (IDH2) | AG-221 | Phase III | [158] |