The identification of drug candidates targeting epigenetic targets, including writers, erasers, and readers, is of large interest for addressing several therapeutic needs. Several epi-drugs currently approved for clinical have been reviewed extensively elsewhere. Similarly, it is attractive identifying probes or tools compounds to understand better epigenetic processes. Among the epigenetic drug and probe candidates, small molecules targeting epigenetic writers such as DNA methyltransferases (DNMTs) and protein lysine methyltransferases (PKMTs) are promising for the treatment of various types of cancer such as colorectal, breast, lung, ovarian, pancreatic cancer and acute myeloid leukemia, neurological disorders, autoimmune diseases, and metabolic diseases. DNA methylation is mediated by the enzyme family DNMTs that is responsible for catalyzing the covalent addition of a methyl group from S-adenosyl-L-methionine (SAM) to the 5-carbon of cytosine, mainly within CpG dinucleotides, yielding S-adenosyl-L-homocysteine (SAH). DNMT3A and DNMT3B are maintenance meanwhile DNMT1 is a de novo methyltransferase. DNMT3A is overexpressed in vulvar squamous cell carcinoma and pituitary adenoma however, it is mainly associated with hematological malignancies such as acute myeloid leukemia, acute lymphocytic leukemia, chronic myelogenous leukemia, chronic myelomonocytic leukemia, and myelodysplastic syndromes. DNMT3B is overexpressed in lung, ovarian, and breast cancer, hepatocellular carcinoma, and mild traumatic brain injury. DNMT1 is associated with colorectal, pancreatic, gastric, lung, and thyroid cancer and pituitary adenoma, lupus, and hereditary sensory neuropathy. Two drugs 1 (5-azacitidine, Vidaza) and 2 (decitabine, 5-aza-20-deoxycytidine, Dacogen) (Figure ) are approved for clinical use to treat the myelodysplastic syndrome. The two drugs are nucleoside analogs that inhibit all three DNMTs (1, 3A, and 3B). Because of the chemical nature of these firstgeneration DNMT inhibitors (DNMTi), these drugs are characterized by substantial cellular and clinical toxicity, which has driven the development of non-nucleoside, novel, and more specific drugs.