Table 1 Anticancer drugs targeting tumor metabolic pathways. The National Clinical Trial (NCT) numbers of anticancer drugs can be found on U.S. National Library of Medicine (https://clinicaltrials.gov/ct2/home). The information was collected until 28th March
Metabolic pathways | Target | Drug | Action mechanism(s) | Clinical stage | Cancer type | References/NCT Number |
|---|---|---|---|---|---|---|
Sugar metabolism | Glucose transporter (GLUT) | Phloretin | GLUT2 inhibitor. Inhibition of glucose transport is related to the earliest steps of apoptosis | Mice/ Preclinical | Liver cancer | (Wu et al. 2009) |
Apigenin | GLUT4 inhibitor, a natural flavonoid with potential antioxidant, anti-inflammatory, and anticancer properties | Clinical Phase II | Colorectal cancer | NCT00609310 | ||
Genistein | GLUT1 inhibitor, a natural flavonoid | Clinical Phase I/II | Colon cancer | NCT01985763 | ||
Naringenin | Glucose transport inhibitor, a natural flavonoid | Preclinical | Colon cancer, prostate cancer | |||
Silybin | Glucose transport inhibitor, a natural flavonoid | Clinical Phase II | Prostate cancer | NCT00487721 | ||
Non-small cell lung cancer (NSCLC) | NCT02146118 | |||||
Resveratrol | GLUT1 inhibitor, a plant antitoxin | Clinical Phase I | Colon cancer | NCT00256334 | ||
Clinical Phase I/II | Liver cancer | NCT02261844 | ||||
Glufosfamide | A novel alkylating agent whose active metabolites are linked to β-d-glucose by glycosidic bonds | Clinical Phase II | Ovarian cancer | NCT00442598 | ||
Hexokinase (HK) | 2-deoxy-d-glucose (2-DG) | Glucose substitute. 2DG-6P inhibits the transformation of G6P to F6P through competitive inhibition of glucose isomerase. | Clinical Phase I/II | Prostate cancer | NCT00633087 | |
3‐Bromopyruvate | Preventing ATP production by limiting the activity of HK in glycolysis | Mice/Preclinical | Glioma | |||
Imatinib | HK inhibitor | Clinical Phase I/II | Gastrointestinal stromal tumors | NCT04138381 | ||
6-Phosphofructo-2-Kinase (PFKFB) | 1-(4-pyridinyl)-3-(2-quinolinyl)-2-propen-1-one (PFK15) | A competitive inhibitor. PFKFB3 catalyzes the reaction to produce fructose 2, 6-diphosphate (F26BP), which is an activator of fructose 6-phosphate 1-kinase, which is a key step in glycolysis. | Mice/Preclinical | Solid tumors, hematologic malignancies | (Clem et al. 2013) | |
Glyceraldehyde 3‐phosphate dehydrogenase (GAPDH) | Iodoacetamide (IAA), Iodoacetate (IA) | GAPDH inhibitor | Preclinical | Glioma | (Schmidt and Dringen 2009) | |
Saframycin A | Forming ternary complexes with GAPDH and DNA, which is toxic to cells | Preclinical | Cervical cancer, lung cancer | (Xing et al. 2004) | ||
Pyruvate kinase (PKM2) | Alkannin | PKM2 inhibitor. PKM2 is widely expressed in cancer cells and determines the final rate-limiting step that is critical to glycolysis for cancer cell proliferation and survival. | Preclinical | Breast cancer | (Chen et al. 2011) | |
Shikonin | PKM2 inhibitor. | Preclinical | Breast cancer | (Li et al. 2014) | ||
Bladder urothelial carcinoma | NCT01968928 | |||||
Lactate dehydrogenase (LDH) | AT-101 | LDHA inhibitor, which inhibits glycolysis and tumor growth, while causing cytotoxicity caused by low intracellular pH | Clinical Phase I/II | Locally advanced esophageal or GE junction cancer | NCT00561197 | |
NHI | LDHA inhibitor | Preclinical | Cervical cancer | (Granchi et al. 2013) | ||
Monocarboxylic acid transporter (MCT) | AZD3965 | MCT1 inhibitor, which inhibits lactate excretion, glycolysis, and tumor growth, while causing cytotoxicity caused by low intracellular pH | Clinical Phase I | Solid tumors, diffuse large B cell lymphoma, burkitt lymphoma | NCT01791595 | |
Quercetin | MCT inhibitor, a natural flavonoid | Clinical Phase I | Prostate adenocarcinoma | NCT01912820 | ||
Luteolin | MCT inhibitor, a natural flavonoid | Clinical Phase I | Tongue carcinoma | NCT03288298 | ||
Pyruvate dehydrogenase (PDH) | Dichloroacetate (DCA) | PDH is a rate-limiting enzyme for aerobic glucose oxidation. DCA stimulation of PDH increases the peripheral oxidation of alanine and lactic acid. | Clinical Phase II | Breast cancer, lung cancer | NCT01029925 | |
CPI-613 | Inhibiting PDH and α-ketoglutarate dehydrogenase, disrupting mitochondrial metabolism | Clinical Phase II | Pancreatic cancer | NCT03699319 | ||
Isocitrate dehydrogenase (IDH) | IDH305 | mIDH1 inhibitor. The mutated IDH (mIDH) alters the catalytic activity of the enzyme to produce oncometabolite 2-hydroxyglutarate (2-HG), thereby regulating the methylation of histone and DNA and promoting the development of tumors. | Clinical Phase II/III | Glioma | NCT02977689 | |
AGI-5198 | The first highly effective, selective IDH1 R132H/R132C mutant inhibitor | Cell/Preclinical | Glioma, colon cancer | (Molenaar et al. 2015) | ||
AG-881 | mIDH1/2 inhibitor | Clinical Phase I | Glioma | NCT02492737 | ||
Enasidenib | mIDH2 inhibitor | Clinical Phase I/II /FDA | Acute myeloid leukemia | NCT04092179 | ||
Glucose-6-phosphate dehydrogenase (G6PDH) | RRx-001 | G6PDH inhibitor. G6PDH is the oxidoreductase of PPP pathway. | Clinical Phase I | Malignant solid tumor, Lymphoma | NCT02096341 NCT01359982 | |
Clinical Phase II | Small cell carcinoma, NSCLC | NCT02489903 | ||||
Imatinib | G6PDH inhibitor | Clinical Phase II | Breast cancer | NCT00193180 | ||
6-phosphate- glucose (G-6-P) | Mannose | Accumulated in cells as mannose-6-phosphoric acid, which damages further glucose metabolism in glycolysis, TCA, PPP, and glycan synthesis | Cell/Preclinical | Ovarian cancer | (Gonzalez et al. 2018) | |
Amino acid metabolism | Glutaminase (GLS) | CB-839 | GLS inhibitor. Glutamine is catalyzed by GLS to glutamate enter TCA. Blocking glutamine enter TCA can inhibit the progression of MYC-driven liver cancer. | Clinical Phase I/II | Lung adenocarcinoma | NCT03875313 |
Phosphoglycerate dehydrogenase, (PHGDH) | CBR-5884 | Inhibiting of de novo serine synthesis in cancer cells, and selective toxicity to cancer cells with high serine biosynthesis activity | Mice/Preclinical | Breast cancer | (Mullarky et al. 2016) | |
Arginine succinic acid synthase (ASS1) | ADI-PEG20 | ASS is the key rate-limiting enzyme for arginine synthesis, which is not expressed in some tumor tissues. ADI-PEG20 is essentially a pegylated, modified arginine deiminase that consumes arginine around the tumor. | Clinical Phase I/Listed | Lung cancer, head and neck squamous cell cancer, prostate cancer | NCT03254732 | |
Recombinant human arginase 1 Peg5000 (rhArgIpeg5000) | The recombinant arginase 1 depletes arginine in the tumor microenvironment. | Clinical Phase I | Lymphoma | NCT01551628 | ||
Asparagine synthase (ASNS) | Asparaginase | Tumor cells lack ASNS and cannot synthesize the asparagine for growth. Asparaginase hydrolyzes asparagine, making the tumor cells lack asparagine, thereby inhibiting growth. | Clinical Phase II /Listed | Acute lymphocytic leukemia, acute myelogenous leukemia, acute mononuclear leukemia | NCT00854425 | |
Indoleamine-2,3-dioxygenase (IDO) | Indoximod and docetaxel | IDO inhibitor. Tryptophan is one of the key amino acids linking anti-tumor immune response and immune tolerance. IDO and TDO are the key enzymes for tryptophan degradation. | Clinical Phase I | Solid tumors, NSCLC | NCT01191216 NCT02460367 | |
Tryptophan-2,3-dioxygenase (TDO) | Indole LM10 | TDO inhibitor | Mice/Preclinical | Mast cell tumor | (Pilotte et al. 2012) | |
Fatty acid metabolism | Acetyl-CoA carboxylase (ACC) | Metformin | Metformin activates AMP-activated kinase (AMPK). ACC is a key enzyme in the de novo fatty acid synthesis pathway. After phosphorylation, ACC activity is lost, which is mainly regulated by AMPK. | Clinical Phase II | Prostate cancer, breast cancer | NCT03137186 NCT01266486 |
ND-646 | An allosteric inhibitor of ACC. Acyl-CoA group was converted into malonyl-CoA through ACC, and decreased the expression of ACC gene could induce apoptosis of cancer cells. | Mouse lung cancer model/ Preclinical | NSCLC | (Svensson et al. 2016) | ||
ATP citrate lyase (ACLY) | SB-204990 | ACLY inhibitor. Reducing cholesterol and fatty acid synthesis | Preclinical | Lung cancer, glioblastoma, colon cancer | (Granchi 2018) | |
SF1126 | Novel inhibitor of PI3 kinase and mTOR | Clinical Phase I | Neuroblastoma | NCT02337309 | ||
Fatty acid synthase (FASN) | TVB-2640, TVB-3166 | Targeted inhibition of FASN can reduce palmitoylation of microtubulin, destroy microtubule tissue, and inhibit the growth of tumor cells. | Clinical Phase II | NSCLC | NCT03808558 | |
C93 | FASN inhibitor | Mice/ Preclinical | NSCLC | (Orita et al. 2007) | ||
Orlistat | FASN inhibitor | Mice/ Preclinical | Melanoma | (Carvalho et al. 2008) | ||
Fatty acyl-CoA synthase (ACS) | Triacsin C | ACS inhibitor. Fatty acids (FA) need to be activated into the active pool by ACS. | Cell/ Preclinical | Glioma | (Mashima et al. 2010) | |
Thiazolidinediones (TZDs) | Interference with TGF-β signal transduction | Cell/ Preclinical | Breast cancer | (Jarrar and Baranova 2007) | ||
Carnitine palmitoyl transferase 1 (CPT1) | Etomoxir | An irreversible CPT1-specific inhibitor, preventing fatty acid transport to the mitochondrial matrix for further metabolism | Mice/ Preclinical | Glioblastoma | ||
Ranolazine | CPT1 inhibitor | Mice/ Preclinical | Prostate cancer | |||
Nucleic acid metabolism | Cytidine deaminase (CDA) | Different oxidation forms of 5-methylcytosine :5hmdC and 5fdC | Conversion into modified uracil inserted into DNA, causing DNA damage and eventually inducing cell to death | Cell/Preclinical | NSCLC | (Zauri et al. 2015) |
Gemcitabine | Cytosine nucleoside derivatives, which incorporate DNA into cells, also inhibit nucleotide reductase, resulting in the reduction of intracellular deoxyriboside triphosphate. | Clinical Phase II | Pancreatic cancer, small cell lung cancer | NCT04039867 | ||
Thymidylate synthase (TS) | 5-fluorouracil (5-FU) | The analogues of uracil, blocking the conversion of deoxyribonucuridine to thymidine and interfere DNA synthesis | Clinical Phase II /Listed | Colon cancer | NCT00388700 | |
Capecitabine | After a series of reactions, its metabolite 5-FU exerts anticancer effects | Clinical Phase IV | Breast cancer, colorectal cancer | NCT03465202 | ||
Folic acid synthesis pathway | Pemetrexed | Folic acid synthesis pathway inhibitor, inhibiting thymidine and purine nucleotide biosynthesis | Clinical Phase I /Listed | NSCLC, pleural mesothelioma | NCT01918761 | |
Dihydrofolate reductase (DHFR) | Aminopterin | DHFR inhibitor | Clinical Phase II | Endometrial carcinoma | NCT00003821 | |
Dihydrowhey acid dehydrogenase (DHODH) | Leflunomide | DHODH inhibitor | Clinical Phase I/II | Breast cancer, multiple myeloma | NCT03709446 NCT02509052 | |
PPRP amido transferase | 6-thioguanine (6-TG) | Purine antagonist, converted to deoxyguanine nucleotides, incorporated into DNA to interfere the function of DNA | Clinical Phase I/II | Acute lymphoblastic leukemia, lymphoblastic lymphoma | NCT02912676 | |
6-thiopurine(6-MP) | Inhibiting the biosynthesis of purines | Clinical Phase II | Breast cancer, ovarian cancer | NCT01432145 | ||
Clinical Phase IV/Listed | Acute lymphocytic leukemia | NCT03920813 | ||||
Topoisomerase II | Banoxantrone(AQ4N) | AQ4N is the prodrug of topoisomerase II inhibitor AQ4 that impedes DNA repair. | Clinical Phase I/II | Non-Hodgkin’s lymphoma, chronic lymphocytic leukemia, small lymphocytic leukemia | NCT00109356 | |
Etoposide | Forming a drug–enzyme–DNA stable reversible complex that impedes DNA repair. | Clinical Phase III/Listed | Small cell lung cancer, malignant lymphoma, malignant germ cell tumor | NCT03305341 |