Table 1.
Inhibitors of tumor metabolism.
| Class of molecules | Inhibitor/trial stage | References | |
|---|---|---|---|
| Preclinical | Clinical | ||
| a) Transporters | |||
| Glucose transporter (GLUT) | Cytochalasin B, naringenin, phloretin, WZB117, thiazolidinedione | Silybin (SIL) (Phase I), resveratrol (Phase II) | Popat et al., 2013; Siegel et al., 2014; Kapoor et al., 2016; Siebeneicher et al., 2016 |
| Sodium-dependent glucose cotransporters (SGLTs) | Dapagliflozin, canagliflozin, and empagliflozin | Lin and Tseng, 2014 | |
| Monocarboxylate transporters (MCTs) | AZD3965 and α-cyano-4-hydroxycinnamic acid | Doherty and Cleveland, 2013; Kumar et al., 2013a; Polański et al., 2014 | |
| Na+/monocarboxylate transport (SMCT) | Ibuprofen, ketoprofen, and fenoprofen | Ganapathy et al., 2008 | |
| Amino acid transporter | 2-Aminobicyclo-(2,2,1)-heptane-2-carboxylic acid | Imai et al., 2010; Huttunen et al., 2016 | |
| Carbonic anhydrase, HCO3 − transporter, Na+/H+ exchanger | KR-33028, acetazolamide, biphenylsulfonamides, brinzolamide, and dorzolamide | Wilex’s cG250 (Rencarex) (Phase I/II) | Morsy et al., 2009; Siebels et al., 2011; Pinard et al., 2013; Amith et al., 2016; Bayat Mokhtari et al., 2017 |
| Vacoular ATPase (V-ATPase) | NiK12192, FR202126 | Pantoprazole (Phase I) | Pérez-Sayáns et al., 2009; Vishvakarma and Singh, 2011; Brana et al., 2014 |
| Glutamine transporter | L-γ-glutamyl-p-nitroanilide | Choi and Park, 2018 | |
| Fatty acid translocase (CD36) | shRNA | Watt et al., 2019 | |
| LDH receptor | shRNA | Gallagher et al., 2017 | |
| b) Signaling messenger/transcription factors | |||
| c-Myc | Mycro3, Mycomycin-2, FBN-1503, 10058-F4 | McKeown and Bradner, 2014 | |
| Sterol regulatory element-binding protein (SREBP) | Betulin, fatostatin, PF-429242, FGH10019 | Hawkins et al., 2008; Kamisuki et al., 2011; Tang et al., 2011; Li et al., 2014b | |
| mTOR | XL765 (Phase I/II), AZD8055 (Phase I/II), NK128/MLN0128 (Phase I/II), Everolimus (Phase II), ridaforolimus (Phase III) | Porta et al., 2014; Xie et al., 2016; Fenner et al., 2019 | |
| PI3K/AKT and mTOR pathways | NVP-BEZ235 | Metformin (Phase III), miltefosine (Phase III) | Porta et al., 2014 |
| c) Metabolic enzymes | |||
| Hexokinase 2 (HK2) | 3-BP, 2-Deoxy-D-glucose | Lonidamine (Phase II) | Oudard et al., 2003; Granchi and Minutolo, 2012; Gandham et al., 2015; Roberts and Miyamoto, 2015; Yadav et al., 2017b |
| Lactate dehydrogenase (LDH) | Sodium oxamate, FX-11, galloflavin | Gossypol (Phase II) | Baggstrom et al., 2011; Doherty and Cleveland, 2013; Zhao et al., 2015b |
| Glutaminase | BPTES, CB-839, compound 968 | Hensley et al., 2013; Choi and Park, 2018 | |
| Glutamate dehydrogenase | Epigallocatechin-3-gallate (Phase I) | Hensley et al., 2013; Zhao et al., 2014 | |
| Acetyl-CoA synthetase II | AR-12/OSU-03012 | Koselny et al., 2016 | |
| Adenosine triphosphate citrate lyase (ACLY) | Hydroxycitrate, radicicol, purpurone, MEDICA | Zu et al., 2012 | |
| Acetyl-CoA carboxylase (ACC) | MK-4074, ND-630, Soraphen-A | Beckers et al., 2007; Harriman et al., 2016; Kim et al., 2017 | |
| Fatty acid synthase (FASN) | Orlistat, cerulenin and its derivative C75 | Epigallocatechin-3-gallate (Phase I) | Kant et al., 2014b; Zhang et al., 2016a; Zhang et al., 2016b |
| Succinate dehydrogenase (SDH) | α-tocopheryl succinate, mitochondrially targeted vitamin E succinate (MitoVES), 3-BP malonate, nitropropionic acid thenoyltrifluoroacetone, troglitazone, atpenin A5 |
Burstein et al., 2003; Kluckova et al., 2013 | |
| Fumarate hydratase | Pyrrolidinone analogs 1–3 | Takeuchi et al., 2015 | |
| Isocitrate dehydrogenase | AG120 and AG221 | Enasidenib (Phase I) | Boddu and Borthakur, 2017; Li et al., 2018 |
| Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) | Koningic acid, methylglyoxal, saframycin A, 3-BP | Ganapathy-Kanniappan et al., 2012; Liberti et al., 2017; Liberti et al., 2019 | |
| Arginine-depleting enzymes | Arginase, arginine decarboxylase, | Arginine deiminase | Patil et al., 2016; Riess et al., 2018 |
| Depletion of amino acids | L-asparaginase | Esen et al., 2016 | |
| Indoleamine 2,3-dioxygenase | Navoximod | Epacadostat (Phase II), indoximod (Phase I), | Brochez et al., 2017; Kristeleit et al., 2017 |
| Oxidative stress inducer | Elesclomol (STA-4783) | O’Day et al., 2013 | |
| Pyruvate dehydrogenase kinase | Dichloroacetate (Phase I) | Chu et al., 2015 | |
| Glutathione (GSH) | Phenethylisothiocyanate (Phase I), Imexon (amplimexon) (Phase II) |
Barr et al., 2014; Yuan et al., 2016 | |
| Isocitrate dehydrogenase 1 (IDH1) | AG-120 (Phase I) | Stein et al., 2014 | |
| HMG-CoA reductase | Statins (Phase III), SWOG0919 (Phase II) |
Advani et al., 2014; Lim et al., 2015; Lee et al., 2017b | |
| d) Other targets | |||
| Vascular endothelial growth factor (VEGF) | Bevacizumab (Phase II),sorafenib (Phase II), sunitinib (Phase II), pazopanib (Phase II) | Moreira et al., 2007; Lane et al., 2009; Li et al., 2014a; Chan et al., 2018; Sato et al., 2018; Sun et al., 2018; Beppu et al., 2019; Fenner et al., 2019 | |