Targeting DNA Methylation with Small Molecules: What’s Next?

Abstract

DNA methylation is a mammalian epigenetic mark that is involved in defining where and when genes are expressed, both in normal cells and in the context of diseases. Like other epigenetic marks, it is reversible and can be modulated by chemical agents. Because it plays an important role in cancer by silencing certain genes, such as tumor suppressor genes, and by reactivating other regions, such as repeated elements, it is a promising therapeutic target. Two compounds are already approved to treat hematological cancers. Many efforts have been carried out to discover new molecules that are able to efficiently inhibit DNA methylation in cancer cells. We will briefly overview the foremost of these efforts by focusing on what we have learned to this point on non-nucleoside inhibitors and on what we consider to be the features of an ideal inhibitor.

Activity landscape of DNA methyltransferase inhibitors bridges chemoinformatics with epigenetic drug discovery

“…As part of the effort to develop epi-drugs and epi-probes, the development of DNA methyltransferase inhibitors (DNMTi) has increased during the last few years [7]. The approval of two DNMTi, 5-azacytidine (azacitidine) and 5-aza-2¢deoxycytidine (decitabine) (Figure 1) for the treatment of myelodysplastic syndrome is a clear example of the therapeutic relevance of DNMTi for the treatment of cancerrelated diseases.…”

“…The approval of two DNMTi, 5-azacytidine (azacitidine) and 5-aza-2¢deoxycytidine (decitabine) (Figure 1) for the treatment of myelodysplastic syndrome is a clear example of the therapeutic relevance of DNMTi for the treatment of cancerrelated diseases. However, the toxicity of these two drugs, their chemical instability, and other issues prompted the search for more specific and non-nucleoside structures [7]. Currently, the development of DNMTs is becoming an area of intense research for a number of therapeutic areas including cancer, Alzheimer's disease and psychiatric conditions, such as depression, bipolar disorder and schizophrenia.…”

Design and synthesis of new non nucleoside inhibitors of DNMT3A

“…13 Their ability to interact with different substrates and some differences in the amino-acid sequence of their respective active sites observed in the crystal structures 14 encourage to consider that it is possible to develop a selective inhibitor for each enzyme, which can be an opportunity to understand the role of each DNMT. 7 This issue could be further explored with this family of compounds Based on these biological properties, a chemical modulation was engaged on the structure of 1 to increase the inhibition activity against DNMT3A. Compound 1 is easily obtained by the synthesis pathway described in Scheme 1…”

“…These inhibitors confirm DNMT as anticancer targets but suffer from poor biodisponibility, toxicity and chemical instability. 7 Several non-nucleosidic inhibitors, such as SGI-1027 or RG108, were described. 8,9 The advantage of this class of inhibitors is that they can offer various selectivity among the DNMT isoforms.…”

Avances en el diseño de fármacos asistido por computadora

“…Es por esto que hay un especial interés para identificar y desarrollar nuevos inhibidores de DNMT que no sean nucleosídicos. A la fecha se conocen diversos iDNMT que se han identificado por métodos diversos y que tienen orígenes diferentes, incluyendo productos naturales, fár-macos obtenidos por reposicionamiento, «hits» de cribado virtual y compuestos de origen sintético (Erdmann, Halby, Fahy y Arimondo, 2014). Dentro de las técnicas computacionales más utilizadas en epigenética se encuentran acoplamiento molecular, modelado por homología (Heinke, Carlino, Kannan, Jung y Sippl, 2011), dinámica molecular (Deschamps, Simões-Pires, Carrupt y Nurisso, 2015) y filtrado computacional (Kuck, Singh, Lyko y Medina-Franco 2010).…”