**3.1 Repurposed drugs for DNMTs**

The alteration of DNA methylation is one of the prominent underlying causes of different diseases. Several market drugs have been shown to lessen disease

progression *via* targeting DNMT, suggesting that those drugs could have newer indications. As summarized in **Table 1**, hydralazine is a hypertensive drug that has been repurposed as both DNMT inhibitor and HDAC inhibitors [76]. In combination with another drug, valproate, hydralazine showed a significant increase in progression-free survival in patients with advanced cervical cancer in a randomized phase II clinical trial [95]. Currently, a phase III clinical trial is underway to examine the effect of hydralazine on AD (NCT04842552). It has been suggested that the stability of polyglutamine repeat expansion, an underlying cause of multiple neurodegenerative diseases, can be caused by hypermethylation of the repeat and the use of hydralazine induces demethylation [96]. This may suggest a mechanism through which hydralazine helps ameliorate AD. Another repurposed drug, procaine, a local anesthetic agent, has been reported to be a potent inhibitor of DNMT activity with an anti-tumor effect in gastric cancer [77]. Procaine has also been shown to exert cardioprotective and neuroprotective effects [78]. Other examples of repurposed drugs that target DNMTs include Procainamide, Mithramycin A, Nanaomycin A, and Disulfiram, etc. [79] (**Table 1**).

Table summarizes the different market approved drugs for other indications known to target epigenetic enzymes in newer indications. The listed drugs are either in preclinical or clinical trial phase for their newer indications.

## **3.2 Repurposed drugs for HDACs**

Among the different classes of epigenetic enzymes, HDAC has the highest number of market-approved inhibitors for diseases, especially in cancer [97]. Vorinostat is the first HDAC inhibitor approved by the FDA for cutaneous T-cell lymphoma (CTCL) treatment [98]. Another HDAC inhibitor, Belinostat, has been granted accelerated approval for treatment of relapsed or refractory peripheral T-cell lymphoma (PTCL) [99]. Also, repurposed drugs that target HDAC are on the rise. One category of drugs that targets HDAC is statins. Statins are a class of medications developed to inhibit 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase for atherosclerosis treatment [100]. Multiple studies have shown that statins exhibit anti-cancer activity and attenuate diabetic nephropathy *via* the inhibition of HDAC [80, 81]. Similarly, the anti-malaria drug artemisinin was reported to exert anti-cancerous effects on breast cancer cells partly *via* the inhibition of HDAC [82]. Through indirect inhibition of HDACs and other epigenetic modifiers, metformin, a type 2 diabetic medication, has been suggested to have a protective effect on cancer, cognitive impairment, and cardiovascular diseases [83]. Carbamazepine, which is approved for the treatment of psychomotor and grand mal seizures, has been reported to inhibit HDAC 3, 6, and 7 and reduce cancer growth in breast, liver, and colon cancer [101]. Currently, trichostatin A (TSA), an approved antifungal drug with HDAC inhibitory activity, is undergoing a phase I clinical trial for relapsed or refractory hematologic malignancies (NCT03838926) (**Table 1**).

#### **3.3 Repurposed drugs for HATs**

The normal levels of gene acetylation can also be restored by HAT inhibitors in diseases. This category of inhibitors is particularly explored as anti-cancer agents, given that inhibiting HATs would only exacerbate cardiovascular and neurodegenerative disease progression. Also, the role of HATs in cancer is context-specific as certain HAT family members can act as oncogenes or tumor suppressors in different tumors. For example, the overexpression of p300/CBP, GCN5, and males absent on the first (MOF) has been shown to sustain cancer hallmarks in glioma, colon, lung cancer, mixed-lineage leukemia (MLL), and acute myeloid leukemia (AML). On the other


#### *Repurposing Market Drugs to Target Epigenetic Enzymes in Human Diseases DOI: http://dx.doi.org/10.5772/intechopen.101397*


**Table 1.** *Examples of repurposed drugs with epigenetic targets in human diseases.*

hand, the deletion of p300/(CREB binding protein) associated factor (pCAF) and Tip60 promotes tumorigenesis in certain cancers [35]. Currently, there have been no investigations into the use of market-approved drugs to target HATs in cancer. Natural compounds targeting HATs, such as anacardic acid, plumbagin, garcinol, and lunasin have been reported to have potent anti-cancer properties [79]. Notably, the progression of HAT inhibitors into clinical trials has been challenging due to the resulting false positive hits gotten from HTS [102]. Thus, more effort is needed to find existing market drugs that not only inhibit HATs activity but also attenuate tumor progression.
