Selected agents targeting metabolism for treatment of various metabolic or inflammatory diseases and cancer
| Drug | Target | Metabolic pathway/consequence | Disease model | Clinical trials/status | Effect on TAMs |
| Glucose metabolism | |||||
| 2-deoxyglucose (2-DG)# | Hexokinase 2 (glucose uptake) | Inhibition of glucose uptake and therefore aerobic glycolysis | Cancer in general, rheumatoid arthritis | Stopped due to toxicity (hypoglycaemia) [102] | Repolarisation [34] |
| Enasidenib (AG-221), AG-120 (Ivosidenib), AGI-5198, AG-881, | Mutant IDH1/2 | Inhibition of α-KG reduction to 2-HG by mutant IDH leading to impaired demethylation | Acute myeloid leukaemia, bile duct cancer, glioma, haematological malignancies, solid tumours [103, 104] | Enasidenib and ivosidenib approved for acute myeloid leukaemia | |
| CB-839 | Glutaminase 1 | Inhibition of glutamin metabolism (increased dependence of glutamine in cancer cells) [105, 106] | Colorectal cancer, NSCLC, renal cell carcinoma, melanoma | NCT03263429, NCT03831932, NCT02771626 | |
| Metformin# | AMPK | Reduction in glycolytic pathway, reduced glucose blood levels, increased FAO, inhibition of respiration, inhibition of mTOR | Type II diabetes, cancer in general, rheumatoid arthritis | Approved for type II diabetes, NCT02019979, NCT02640534, NCT01310231, NCT02312661 | Repolarisation [97, 98] |
| Nucleotide biosynthesis | |||||
| Methotrexate, Pemetrexed | DHFR, GARFT | Impaired nucleotide biosynthesis | Breast cancer | Phase II trial (methodextrate) | |
| Amino acid metabolism | |||||
| L-asparaginase (Elspar, Kidrolase), PEG-BCT-100 (ADI-PEG20), AEB-1102 | Circulating arginine | Breakdown of arginin, targeting cancer cells without ability for arginase de novo synthesis (ASS1 silenced cancer types) | Melanoma, hepatocellular carcinoma, acute lymphocytic leukaemia | L-asparaginase approved for acute lymphocytic leukaemia | |
| Rapamycin, RAD001# | mTOR | Deregulation of proliferation and protein/lipid/nucleotide production | ALS, glioma, NSCLC | NCT03359538, NCT01158651, NCT01063478 | Repolarisation [95, 96] |
| L-norvaline, CB-1158# | Arginase 1 | Disruption of de novo arginine synthesis | Advanced solid tumours, Alzheimer's disease models [107] | Repolarisation [47] | |
| PHGDH inhibitors | Phosphoglycerate dehydrogenase | De novo serine synthesis | Breast cancer, lung adenocarcinoma, melanoma [108–110] | ||
| Lipid metabolism | |||||
| ND-646 | ACC | Impaired de novo fatty acid synthesis | Lung tumour models [82] | ||
| Pralnacasan, NCX-4016, YVAD, VAD# | Caspase-1 | Inhibition of inflammasome/lipid accumulation in inflammatory cells | Rheumatoid arthritis, osteoarthritis, inflammatory bowel disorders, cancer, autoimmune diseases | Pralnacasan studies stopped after phase II | Specifically targets and repolarises TAMs [82] |
| Paclitaxel, Methodextrate, Doxorubicin# | ABC transporter | Impaired efflux leading to accumulation of e.g. xenobiotics or cholesterol in the cell | Multidrug resistant cancer [91] | Studies ongoing e.g. phase III trial for breast cancer (NCT02488967) | Repolarisation [90] |
| Meclofenamate sodium, Zileuton# | 5-LOX | Conversion of arachidonic acid to 5-HETE and leukotrienes | Pain relief, rheumatoid arthritis, osteoarthritis, asthma | TME infiltration [79] |
TAM: tumour-associated macrophages; IDH: isocitrate dehydrogenase; α-KG: α-ketoglutarate; 2-HG: 2-hydroxyglutaric acid; NSCLC: nonsmall cell lung cancer; AMPK: AMP-activated protein kinase; FAO: fatty acid oxidation; mTOR: mammalian target of rapamycin; DHFR: dihydrofolate reductase; GARFT: glycinamide ribonucleotide formyltransferase; ALS: amyotrophic lateral sclerosis; ACC: acetyl-CoA carboxylase; TME: tumour microenvironment; 5-LOX: 5-lipoxygenase; 5-HETE: 5-hydroxyeicosatetraenoic acid. #: potential specific TAM metabolic targets.