DNA methylation occurs at the C5 of cytosine ring, mostly in a CpG dinucleotides context, by transfer of a methyl group from S-adenosyl-L-methionine and is catalyzed by three DNA methyltransferases (DNMTs): DNMT1, DNMT3A, DNMT3B. DNA methylation is a crucial epigenetic modification in modulation of gene expression and it is involved in various physiological processes such as genomic imprinting, chromosome X inactivation, gene silencing, chromosomes stability and repression of transposons. Thus abnormal activity of DNMTs is described in several diseases included cancer. So far, several nucleoside (N) and non-nucleoside (NN) DNMT inhibitors (DNMTi) have been described and studied for their activity against cancer. Two azanucleosides have been approved for the treatment of haematological malignancies but, despite their efficacy, poor bioavailability, chemical instability and severe side-effects have been detected. On the other hand, the non-nucleoside DNMTi available to date, even if less toxic than aza-nucleosides, exhibit low potency and poor specificity for DNMTs, so that none of them is studied for clinical applications. Therefore the discovery of novel, potent and selective non-nucleoside DNMTi still remains an important challenge. SGI-1027 has been described as potent NN-DNMTi able to induce demethylation and re-express Tumor Suppressor Genes (TSGs) silenced by methylation in RKO cancer cells. Recently the group of Prof. A. Mai described MC3343, MC3353, MC2838 and MC2835, a group of DNMTi analogues of SGI-1027, able to inhibit proliferation in several cancer cell lines at µM concentrations. Moreover, tested in peripheral blood mononuclear cells (PBMCs), MC3343 was reported to possess a lower toxicity compared to the SGI-1027.The aim of this project is to further optimize activity, and improve potency and selectivity, of this series of DNMTi.
During our investigation of small molecule epigenetic modulators, we described various series of compounds able to inhibit DNMTs. In particular, chemical manipulation of SGI-1027 led to obtain some potent derivatives, such as MC3343, MC3353, MC2838 and MC2835 able to inhibit the proliferation in several cancer cell lines (U937, MDA-MB-231, RAJI e PC3). Unlike SGI-1027, MC3343 showed to inhibit DNMT1 with a SAM non-competitive mechanism and, interestingly, this compound displayed the highest antiproliferative effect in PBMCs and also inhibits proliferation in MbSCs.8 Nowadays, NN-DNMTi are in development to address high toxicity of nucleoside analogs. However, these compounds still have low activity in cancer cells and mode of action of these compounds remains unclear.13 Therefore, with the aim to improve the potency and the anticancer effects of our derivatives, in this study we will apply several structural modifications, working on MC3343, MC3353, MC2838 and MC2835 scaffolds in order to confer them drug-like properties. Moreover, the discovery of a novel, potent and selective NN-DNMTi will allow to overcome the major limitations of the current NN-DNMTi reported in literature (i.e low potency, poor solubility, high toxicity) and hopefully to find an effective anticancer treatment.
References
1) Goldberg A.D.et al., Cell,2007; 128, 635-8.
2) Jurkowska R.Z. et al., ChemBioChem, 2011; 12, 206-22.
3) Gros C. et al., Biochemie, 2012; 94, 2280-96.
4) Okano M. et al., Cell, 1999, 99, 247-57.
5) Liang G., et al., Mol.Cell.Biol., 2002, 22, 480-91.
6) Daniel F.I., et al., Cancer, 2011, 117, 677-87.
7) Esteller M., N. Engl. J. Med., 2008, 358, 1148-1159.
8) Valente S., et al., J.Med.Chem., 2014, 57, 701-713.
9) Jung Y., et al., J. Mol. Med., 2007, 85, 1137-48.
10) Zheng Y. G., et al., Med. Res. Rev., 2008, 28, 645-87.
11) Yang X., et al., Trends Pharmacol. Sci., 2010, 31, 536-46.
12) Datta J., et al., Cancer Res., 2009, 69, 4277-85.
13) Graça I., et al., Curr Pharm Des. 2014, 20, 1803-11.