Table 6.

Current HAT HMT, HDM, and BET inhibitors repurposed with epigenetic applications in cancer therapy [*modified from Moreira-Silva et al., (9)].

Class	Compound	First indication	Epigenetic target	Drug-target interaction	Cancer model/New indication	Key features in mechanism	References
HAT, HMT, HDM, and BET inhibitors
HATi	Anacardic acid	Anti‐inflammatory; food-derived (not approved)	HAT/Ep300 and Tip60	Not described	Cervical Tumor cells	Inhibits Tip60 HAT and ATM acetylation. Promotes resensitizing tumor cells to the cytotoxic effect of radiation.	(246)
					Myeloid Leukemia cells	Inhibits p300 HAT activity. Also, inhibits NF-kB activation, inhibits IkBalfa activation, p65 acetylation and nuclear translocation. It potentiates apoptosis via TNF-induced caspase activation and suppresses the expression of genes involved in invasion and angiogenesis.	(247, 248)
					T‐Cell Lymphoma cells
					Lung Cancer cells
					Prostate Cancer cells
	Garcinol	Antioxidant benzophenone (not approved);	HAT2B/Ep300	Not described	Cervical Cancer cells	Inhibits p300 and KAT2B activity, HAT activity and induces apoptosis.	(249)
					Breast Cancer cells	Decreases H3K18 acetylation and increases DNA damage signaling markers. Inhibits HAT activity and induces cell proliferation arrest.	(250)
					Hepatocellular Carcinoma cells	Decreases HAT activity and inhibits STAT3 activation through acetylation. Decreases proliferation, tumor growth, survival and angiogenesis.	(251)
					Esophageal Carcinoma cells	Decreases p300/CBP levels, induces cell cycle arrest, thus induces apoptosis and inhibits migration and cell invasion and proliferation. Inhibits metastasis and inhibit HAT and its cofactors, decreasing TGF-beta pathway.	(252)
	Plumbagin	Nutraceutical quinone (not approved);	HAT3B/p300	Inhibits p300 HAT activity (non-competitive), through a single hydroxyl group of plumbagin that makes a hydrogen bond with the lysine 1358 residue of the p300 HAT domain.	Liver Carcinoma cells	Inhibits p300 HAT activity AND inhibits p300-mediated acetylation of p53 AND reduces H3 and H4 acetylation AND induces apoptosis AND modulates the enzymatic activity of p300. in vivo: reduces H3 acetylation.	(253)
	Lunasin	Natural Compound; food-derived peptide	HAT	Not described. Possibly a competitive inhibitor	Cancer preventive in mouse Fibroblasts	Suppresses foci formation in mice fibroblast cells induced by chemical carcinogens by the RGD motif and its chromatin-binding property, binding to deacetylated histones, and the reduction of histone acetylation.	(254)
HMTi	Allantodapsone	Antibiotic (Dapsone-derivated)	H4R3me	Inhibitory activity toward PRMT1	Hepatocellular Carcinoma cells	Inhibits cellular H4R3 methylation to the same level as AMI-1, while the H3K4 methylation level is barely impacted.	(255)
	Ribavirin	RSV infections and Hepatitis C	EZH2	Not described. Possibly a selective inhibitor of EZH2	Solid Tumors (Atypical teratoid/rhabdoid tumor)	Inhibits cell growth, induces cell cycle arrest and apoptosis. Also inhibits eIF4E and EZH2 activity decreasing its expression levels. Impairs cell migration, invasion and adhesion. In osteosarcoma enhances chemosensitivity.	(230, 256)
					Breast, Brain, Cervical, Colon and Prostate Cancer cells	Decreases EZH2 expression, inhibits HMT activity and decreases H3K27me3. Induces variable growth inhibition and downregulation of EZH2, eIF4E and IMPDH1.	(257)
	Hydroxychloroquine (HCQ)	Antimalarial/Arthritis	PRC2	Disruption of PRC2-EED complex by allosteric PRC2-EED binding inhibition within the H3K27me3-binding pocket, thus antagonizing the PRC2 catalytic activity	Multiple Myeloma Cells	Decreases H3K27me3 levels in MM cells 3 by disrupting the H3K27me3- EED interaction within the PRC2 complex. Suggesting that its anti-tumor activity might rely on the reactivation of genes abnormally silenced via H3K27 hypermethylation.	(258)
HDMi	Clorgyline	MAO inhibitor	LSD1	Not described	Bladder Cancer cells	Induces DNA demethylation, inhibits LSD1, decreasing H3K4me2 and H3K4me, establishes an active chromatin state. Inhibits cell growth induces the expression of previously silenced genes by enriching H3K4me2 and H3K4me1 histone marks.	(259)
					Colon Cancer cells
					Promyelocytic Leukemia Cells
	Geranylgeranoic acid	Natural Compound (not approved)	LSD1	Not described	Neuroblastoma cells	Inhibits LSD1 activity, induces NTRK2 gene expression and increases H3K4me2. Moreover decreases cell proliferation.	(260)
	Pargyline	MAO‐B inhibitor; antihypertensive	LSD1	Not described	Prostate Cancer cells	Inhibits cell migration and invasion AND inhibit EMT AND induces E-cadherin expression AND inhibits N-cadherin and Vimentin expression AND delayed PCa transition to CRPC AND decreases PSA expression AND decreases H3K4 and H3K9 di-methylation.	(261)
	Tranylcypromine	Severe depression	LSD1	Not described	Glioblastoma cells	Induces cell death AND inhibits LSD1 activity AND increases cell sensitivity to HDACi.	(262, 263)
	Polymyxin A/B	Antibiotic	LSD1	Inhibits LSD1 by competition with its substrate at the enzyme’s cleft entry	Chemical inhibition of LSD1 assay	In vitro assays demonstrated that quinazoline core can represent a privileged scaffold for developing inhibitors that target epigenetic enzymes.	(264)
BETi	Azelastine	Anti-histaminic	BET-BRD4	Inhibits BRD4 through interactions with several key residues of the acetyl lysine binding pocket	Structural in silico assays by docking-based method	Docking-based database screening identified Azelastine drug as a promising novel template exhibiting binding affinity better than the control lead (+)-JQ1 for the human BRD4. Azelastine is having a low molecular weight, which gives a scope of further chemical modification to enrich its binding affinity for BRD4.	(265)
	Nitroxoline	Antibiotic	BET-BRD4	Occupies the acetylated lysine binding pocket of the first bromodomain of BRD4	MLL Leukemia cells	Prevents the binding of BRD4 to acetylated H4	(266)