Table 1. Reversal of epigenetic dysregulation by targeting cancer metabolism.
| Inhibitor | Target enzyme | Mode of action | Ongoing clinical use/trials | Ref |
|---|---|---|---|---|
| Glycolysis inhibitors | ||||
| 2-Deoxyglucose (2-DG) | Hexokinases | 2-DG inhibits hexokinase, a rate limiting enzyme for glycolysis. 2-DG suppressed acetyl-CoA levels, and reduced the acetylation of histone H3, H4, H2A and H2B in multiple cancer cell lines | 2-Deoxyglucose (Phase I/II) | 164, 165 |
| 3-Bromopyruvate (BrPA) | Glyceraldehyde 3-phosphate dehydrogenase | BrPA inhibits GAPDH and acetyl-CoA production BrPA suppressed histone acetylation and induced differentiation of embryonic stem cells | NA | 166 |
| Glutaminolysis inhibitors | ||||
| Bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl) ethyl sulfide (BPTES), CB-839, Compound 968, Zaprinast | Glutaminase (GLS) | GLS inhibitors suppress acetyl CoA and 2-HG production Compound 968 reduced histone H3K4me3 in breast cancer cells. Zaprinast decreased H3K9me2/3 in IDH1-mutant cancer cells | CB-839 (Phase I) | 167, 168, 169, 170, 171 |
| IDH1 inhibitors | ||||
| AG-120, AG-881, AGI-5198, BAY1436032, bis imidazole phenol, FT-2102, GSK321, GSK864, 1-Hydroxypyridin-2-one compounds, IDH305, ML309, 2-(3-Trifluoromethylphenyl)isothioazol-3(2H)-one | Mutant IDH1 | IDH1 inhibitors suppressed 2-HG production in IDH1 mutant cells. AGI-5198 induced demethylation of H3K9me3 and H3K27me3 in IDH1-mutant chondrosarcoma cells. GSK321 induced genome-wide DNA hypomethylation in IDH1 mutant acute myeloid leukemia cells | AG-120±Azacitidine (Phase I/II), AG-881 (Phase I), BAY1436032 (Phase I), FT-2102±Azacitidine (Phase I), IDH305 (Phase I) | 172, 173, 174, 175, 176, 177, 178 |
| IDH2 inhibitors | ||||
| AG-221, AG-881, AGI-6780 | Mutant IDH2 | IDH2 inhibitors suppressed 2-HG production in IDH2-mutant cells. Both AG-221 and AGI-6780 induced demethylation of DNA and histone marks in IDH2-mutant leukemia cell lines | AG-221±Azacitidine (Phase I/III), AG-881 (Phase I) | 179, 180, 181, 182, 183, 184 |
| SAM cycle inhibitors | ||||
| DZNep (3-deazaneplanocin A), adenosine dialdehyde | SAH hydrolase | DZNep and adenosine dialdehyde increased the SAH-to-SAM ratio and inhibited DNA and histone methylation in cancer cell lines | NA | 185, 186, 187, 188, 189, 190 |
| NNMT inhibitor | ||||
| N-Methylnicotinamide | Nicotinamide N-methyl-transferase (NNMT) | N-methylnicotinamide increased SAM level and histone methylation in NNMT-overexpressing cancer cells | NA | 191 |
| Hexosamine biosynthesis pathway inhibitors | ||||
| O-Diazoacetyl-L-serine (azaserine), 6-Diazo-5-oxo-L-norleucine (DON) | Glutamine-Fructose-6-Phosphate Transaminase | Azaserine and DON decreased protein O-GlcNAcylation levels | NA | 192 |
Abbreviation: NA, not applicable.