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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

From: Leveraging and manufacturing in vitro multicellular spheroid-based tumor cell model as a preclinical tool for translating dysregulated tumor metabolism into clinical targets and biomarkers

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 (Harmon and Patel 2004; Lim et al. 2017)
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 (Bodur et al. 2016; El Sayed et al. 2012)
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 (Pike et al. 2011; Samudio et al. 2010)
Ranolazine CPT1 inhibitor Mice/
Preclinical
Prostate cancer (Deep and Schlaepfer 2016; Samudio et al. 2010)
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
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