Table 1.
Therapeutic strategies for targeting cancer metabolism.
| Agent | Pathway/Target | Mode of Action | Stage of Drug Development | Reference |
|---|---|---|---|---|
| Targeting Aerobic Glycolysis and Pyruvate Metabolism | ||||
| WZB117 | GLUT1 | Inhibition of glucose uptake | Preclinical | [225] |
| STF-31 | GLUT1 | Preclinical | [226] | |
| Fasentin | GLUT1 | Preclinical | [227,228] | |
| Polyphenol phloretin | GLUT2 | Preclinical | [229,230] | |
| Flavonoids (myricetin, fisetine, quercetin, isogquercitrin) | GLUT2 | Preclinical or in market for the treatment of hematopoietic/lymphoid or solid cancer | [231] | |
| Ritonavir | GLUT4 | On the market for the treatment of multiple myeloma | [232,233] | |
| KU-55933 | ATM/GLUT1 | Preclinical | [234] | |
| Resveratrol | Akt/mTOR/GLUT1 | Preclinical | [235] | |
| 2-deoxyglucose (2-DG) | Hexokinase 2 (HK2) | Inhibition of glycolysis | Clinical trial phase 2 for the treatment of advanced cancer and hormone refractory prostate cancer | [236,237] |
| 3-bromopyruvate (BrPA) | Preclinical | [238,239] | ||
| Lonidamine | Clinical trial phase 3 for the treatment of breast cancer | [240,241] | ||
| Genistein (GEN)-27 | On the market for the treatment of breast cancer | [242,243] | ||
| Benserazide | On the market for the treatment of colon cancer | [244] | ||
| Natural products (astragalin, resveratrol, chrysin) | Preclinical or in market | [245,246] | ||
| 3PO | 6-phosphofructo-2-kinase (PFKB3) | Inhibition of glycolysis | Preclinical | [247,248] |
| PFK15 | Preclinical | [248] | ||
| Koningic acid (KA) | Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) | Inhibition of glycolysis | Preclinical | [249,250] |
| DC-5163 | Preclinical | [251] | ||
| Methylglyoxal (MG) | Clinical trial phase 3 for the treatment of myelocytic leukemia and lymphomatous disease | [252] | ||
| TT-232 | Pyruvate kinase type M2 (PKM2) |
Inhibition of glycolysis and induction of apoptosis | Clinical trial phase 2 for the treatment of renal cell carcinoma | [253] |
| Shikonin | Preclinical | [254] | ||
| Vitamin K(3) and K(5) | Clinical trial phase 1 | [255] | ||
| Oleanolic acid (OA) | Preclinical | [256] | ||
| CPI-613 | Pyruvate dehydrogenase (PDH) and α-ketoglutarate dehydrogenase | Inhibition of mitochondrial metabolism | Clinical trial phase 3 for the treatment of pancreatic cancer | [257,258] |
| Dichloroacetate (DCA) | Pyruvate dehydrogenase kinase (PDK) | Shifting from glycolysis to oxidative phosphorylation | On the market for the treatment of glioblastoma multiforme | [259,260,261] |
| Mitaplatin | Preclinical | [262,263] | ||
| Betulinic acid (BA) | Clinical trial phase 2 for the treatment of colon cancer | [264] | ||
| Oxamate | Lactate dehydrogenase A (LDHA) | Pyruvate competitive | Preclinical | [265,266] |
| Gossypol | NADH competitive | Phase 1~3 for the treatment of glioblastoma multiforme | [267,268] | |
| FX11 | NADH competitive | Preclinical | [269] | |
| N-hydroxyindoles (NHI) | Pyruvate and NADH competitive | Preclinical | [270] | |
| Galloflavin (GF) | Binding of free enzyme | Preclinical | [271] | |
| AZD3965 | Monocarboxylate transporter (MCT1) | Inhibition of glycolysis | Clinical trial phase 1 | [272] |
| Targeting Pentose Phosphate Pathway | ||||
| Dehydroepiandrosterone (DHEA) | Glucose-6-phosphate dehydrogenase (G6PD) | Inhibition of glycolysis and induction of apoptosis | On the market for the treatment of breast cancer and prostate cancer | [273,274] |
| 6-aminonicotinamide (6-AN) |
Preclinical | [275] | ||
| Polydatin | Clinical trial phase 2 for the treatment of hepatocellular carcinoma | [276,277] | ||
| Targeting Serine Biosynthesis Pathway | ||||
| CBR-5884 | 3-phosphoglycerate dehydrogenase (PHGDH) | Inhibition of de novo serine synthesis | Preclinical | [278] |
| NCT-503 | Preclinical | [279] | ||
| Targeting Glutamine Metabolism and Mitochondrial TCA cycle | ||||
| V-9302 | ASCT2 (SCL1A5) | Inhibition of glutamine transport | Preclinical | [280,281] |
| GPNA | Preclinical | [282] | ||
| Benzylcysteine | Preclinical | [283] | ||
| Benzylserine | Preclinical | [284] | ||
| BCH | LAT1 (SCL7A5) | Inhibition of glutamine-essential amino acid transport | Preclinical | [285] |
| DON | Glutamine-utilizing enzymes, including glutaminase | Glutamine antagonist | Clinical trial phase 3 for the treatment of advanced refractory solid tumors | [286] |
| JHU-083 | Preclinical | [287,288] | ||
| Rais-5C | Preclinical | [289] | ||
| Nedelcovych-13d | Preclinical | [290] | ||
| JHU-395 | Preclinical | [291] | ||
| Sirpiglenastat (DRP-104) | Clinical trial phase 2 for the treatment of glioblastoma | [292] | ||
| BPTES | Glutaminase (GLS1) | Allosteric inhibitor mTOR signaling downregulation and inhibition of TCA anaplerosis |
Preclinical | [293,294] |
| CB-839 | Clinical trial phase 2 for the treatment of triple-negative breast cancer | [295,296] | ||
| Compound 968 | Preclinical | [297,298] | ||
| Alkyl benzoquinones | Glutaminase (GLS2) | mTOR signaling downregulation and active autophagy | Preclinical | [299] |
| Thiazolidine-2,4-dione | Glutaminase (GLS1 and GLS2) | Moderately more selective for GLS1 than GLS2 | On the market for the treatment of lung cancer | [300] |
| Amino oxyacetate (AOA) | Transaminase | Glutaminolysis inhibition in Myc driven tumors | Preclinical | [131] |
| Epigallocatechin gallate (EGCG) | Glutamate dehydrogenase (GLUD1) | Decreased glutathione peroxidase activity | On the market for the treatment of glioblastoma | [131,301] |
| R162 | Preclinical | [302] | ||
| UK5099 | Mitochondrial pyruvate carrier (MPC) | Inhibition of pyruvate transport | Preclinical | [303] |
| Targeting Fatty acid Metabolism | ||||
| Etomoxir | Carnitine palmitoyl transferase 1 (CPT1) | Inhibition of fatty acid oxidation | Preclinical | [304,305,306] |
| BMS-303142 | ATP citrate lyase (ACLY) | Inhibition of de novo lipid synthesis | Preclinical | [307] |
| SB-204990 | Preclinical | [308] | ||
| Soraphen A | Acetyl-CoA carboxylase (ACC) | Preclinical | [309] | |
| ND-646 | Preclinical | [310] | ||
| Cerulenin | Fatty acid synthase (FASN) | Preclinical | [311,312] | |
| TVB-2640 | Clinical trial phase 2 for the treatment of lung cancer, breast cancer, ovarian cancer | [313] | ||
| Orlistat | On the market for the treatment of gliomas and T cell lymphoma | [314,315] | ||
| C75 | Clinical trial phase 2 for the treatment of prostate cancer | [316] | ||
| CAY10566 | Stearoyl-CoA desaturase 1 (SCD1) | Preclinical | [317] | |
| A939572 | Preclinical | [318,319] | ||
| Fatostatin | Sterol regulatory element binding protein 1 (SREBP-1) |
Preclinical | [320,321] | |
| Betulin | Preclinical | [322] | ||
| PF-429242 | Preclinical | [323] | ||
| MSI-1 | Preclinical | [324] | ||
| Targeting Isocitrate Dehydrogenase (IDH) | ||||
| AG-120 (ivosidenib) | IDH1 | DNA and histone hypermethylation | Clinical trial phase 3 for the treatment of cholangiocarcinoma | [325,326] |
| AG-221 (enasidenib) | IDH2 | Clinical trial phase 3 for the treatment of refractory and relapsed acute myeloid leukemia | [327,328,329] | |
| IDH305 | IDH1 | Clinical trial phase 2 for the treatment of leukemia | [330] | |
| AG-881 (vorasidenib) | IDH1/2 | Clinical trial phase 3 for the treatment of glioma | [331,332] | |
| FT-2102 (olutasidenib) | IDH1 | Clinical trial phase 2 for the treatment of relapsed or refractory glioma | [333,334] | |
| BAY1436032 | IDH1 | Clinical trial phase 1 | [335] | |