Discovery and Optimization of Inhibitors of DNA Methyltransferase as Novel Drugs for Cancer Therapy

The genome contains genetic and epigenetic information. While the genome provides the blueprint for the manufacture of all the proteins required to create a living thing, the epigenetic information provides instruction on how, where, and when the genetic information should be used (Robertson, 2001). The major form of epigenetic information in mammalian cells is DNA methylation that is the covalent addition of a methyl group to the 5-position of cytosine, mostly within the CpG dinucleotide (Robertson, 2001). DNA methylation is involved in the control of gene expression, regulation of parental imprinting and stabilization of X chromosome inactivation as well as maintenance of the genome integrity. It is also implicated in the development of the immune system, cellular reprogramming and brain function and behaviour (Jurkowska et al., 2011). DNA methylation is mediated by a family of DNA methyltransferase enzymes (DNMTs). In mammals, three DNMTs have been identified so far in the human genome, including the two de novo methyltransferases (DNMT3A and DNMT3B) and the maintenance methyltransferase (DNMT1), which is generally the most abundant and active of the three (Goll and Bestor, 2005; Robertson, 2001; Yokochi and Robertson, 2002). DNMT3L is a related protein that has high sequence similarity with DNMT3A, but it lacks any catalytic activity owing to the absence of conserved catalytic residues. However, DNMT3L is required for the catalytic activity of DNMT3A and 3B (Cheng and Blumenthal, 2008). The protein DNMT2 can also be found in mammalian cells. Despite the fact that the structure of DNMT2 is very similar to other DNMTs, its role is comparably less understood (Schaefer and Lyko, 2010). It has been reported that DNMT2 does not methylate DNA but instead methylates aspartic acid transfer RNA (tRNAAsp) (Goll et al., 2006). Recent evidence suggests that DNMT2 activity is not limited to tRNAAsp and that DNMT2 represents a noncanonical enzyme of the DNMT family (Schaefer and Lyko, 2010). DNMT1 is responsible for duplicating patterns of DNA methylation during replication and is essential for mammalian development and cancer cell growth (Chen et al., 2007). These enzymes are key regulators of gene transcription, and their roles in carcinogenesis have been the subject of considerable interest over the last decade (Jones and Baylin, 2007; Robertson, 2001). Therefore, specific inhibition of DNA methylation is an attractive and novel approach for cancer therapy (Kelly et al., 2010; Lyko and Brown, 2005; Portela and