Selected agents targeting metabolism for treatment of various metabolic or inflammatory diseases and cancer

DrugTargetMetabolic pathway/consequenceDisease modelClinical trials/statusEffect on TAMs
Glucose metabolism
 2-deoxyglucose (2-DG)#Hexokinase 2 (glucose uptake)Inhibition of glucose uptake and therefore aerobic glycolysisCancer in general, rheumatoid arthritisStopped due to toxicity (hypoglycaemia) [102]Repolarisation [34]
 Enasidenib (AG-221), AG-120 (Ivosidenib), AGI-5198, AG-881,Mutant IDH1/2Inhibition of α-KG reduction to 2-HG by mutant IDH leading to impaired demethylationAcute myeloid leukaemia, bile duct cancer, glioma, haematological malignancies, solid tumours [103, 104]Enasidenib and ivosidenib approved for acute myeloid leukaemia
 CB-839Glutaminase 1Inhibition of glutamin metabolism (increased dependence of glutamine in cancer cells) [105, 106]Colorectal cancer, NSCLC, renal cell carcinoma, melanomaNCT03263429, NCT03831932, NCT02771626
 Metformin#AMPKReduction in glycolytic pathway, reduced glucose blood levels, increased FAO, inhibition of respiration, inhibition of mTORType II diabetes, cancer in general, rheumatoid arthritisApproved for type II diabetes,
NCT02019979, NCT02640534, NCT01310231, NCT02312661
Repolarisation [97, 98]
Nucleotide biosynthesis
 Methotrexate, PemetrexedDHFR, GARFTImpaired nucleotide biosynthesisBreast cancerPhase II trial (methodextrate)
Amino acid metabolism
 L-asparaginase (Elspar, Kidrolase), PEG-BCT-100 (ADI-PEG20), AEB-1102Circulating arginineBreakdown of arginin, targeting cancer cells without ability for arginase de novo synthesis (ASS1 silenced cancer types)Melanoma, hepatocellular carcinoma, acute lymphocytic leukaemiaL-asparaginase approved for acute lymphocytic leukaemia
 Rapamycin, RAD001#mTORDeregulation of proliferation and protein/lipid/nucleotide productionALS, glioma, NSCLCNCT03359538, NCT01158651, NCT01063478Repolarisation [95, 96]
 L-norvaline, CB-1158#Arginase 1Disruption of de novo arginine synthesisAdvanced solid tumours, Alzheimer's disease models [107]Repolarisation [47]
 PHGDH inhibitorsPhosphoglycerate dehydrogenaseDe novo serine synthesisBreast cancer, lung adenocarcinoma, melanoma [108–110]
Lipid metabolism
 ND-646ACCImpaired de novo fatty acid synthesisLung tumour models [82]
 Pralnacasan, NCX-4016, YVAD, VAD#Caspase-1Inhibition of inflammasome/lipid accumulation in inflammatory cellsRheumatoid arthritis, osteoarthritis, inflammatory bowel disorders, cancer, autoimmune diseasesPralnacasan studies stopped after phase IISpecifically targets and repolarises TAMs [82]
 Paclitaxel, Methodextrate, Doxorubicin#ABC transporterImpaired efflux leading to accumulation of e.g. xenobiotics or cholesterol in the cellMultidrug resistant cancer [91]Studies ongoing e.g. phase III trial for breast cancer (NCT02488967)Repolarisation [90]
 Meclofenamate sodium, Zileuton#5-LOXConversion of arachidonic acid to 5-HETE and leukotrienesPain relief, rheumatoid arthritis, osteoarthritis, asthmaTME 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.