1. INTRODUCTION.
The control of chromatin structure mediated by epigenetic mechanisms has an accepted role in the control of gene expression and other DNA-related biological processes. DNA methylation/demethylation and post-translational modifications of histones set an epigenetic landscape that is stable during cell replication and that could be modulated by specific environmental signals to guide normal development and cell differentiation (Allis and Jenuwein, 2016; Dai et al., 2020). This orchestrated setting is also subject to deviations. Epigenetic alterations are associated with multiple human disorders, includingde novo epimutations (e.g., cancer, neurological disorders, infectious diseases or cardiovascular pathologies) but also germline-related diseases (e.g. rare disorders associated with genetic mutations affecting epigenetic modifiers) (Berdasco and Esteller, 2018). Our knowledge of epigenetic alterations in disease has improved the discovery and development of small-molecule compounds targeting the catalytic pocket of enzymes with epigenetic activity (Ganesan et al., 2019; Jones et al., 2019). The range of small-molecule inhibitors that target epigenetic proteins include enzymes that add chemical groups into DNA and histones (“writers ”), proteins that remove these chemical tags (“erasers” ) and specific binding domain proteins that are able to identify and interpret these modifications (“erasers” ) (Ganesan, 2018; Ganesan et al., 2019). DNA methyltransferase (DNMT) inhibitors such as decitabine have been implemented into clinical practice for the treatment of haematological malignancies, such as myelodysplastic syndromes (MDS), acute myeloid leukaemia (AML), and chronic myeloid leukaemia (CML) (Prebet et al., 2014; Diesch et al., 2016). Similarly, histone deacetylase (HDAC) inhibitors have also reached FDA- approval for clinical routine in refractory CML Panobinostat) (Cavenagh and Popat, 2018). New approaches in epidrug development explore the presence of genetic mutations of epigenome-modifying enzymes as a more targeted therapy (Cossío et al., 2020). In this line, the histone methyltransferase (HMT) EZH2 inhibitor tazemotostat reached a Phase II/III clinical trial to treat refractory non-Hodgkin lymphoma with EZH2 amplification (Italiano et al., 2018) or the DOT1L inhibitor pinometostat for the treatment of MLL-fusion leukaemia (Stein et al., 2018). Opportunities have extended beyond cancer and the potential of epigenetic drugs as therapeutic agents able to revert epigenetic defects is extending to other pathologies, ranging from infectious diseases to brain diseases, cardiovascular and metabolic disorders (Ballestar and Li, 2017; Berdasco and Esteller, 2019; Villanueva et al., 2020). The volume of epigenetic research conducted in academia, R&D sector of pharmaceutical industry and biotech companies have boosted the epigenetic-based market.
Following the epigenetic model, recent discoveries on the role of post-translational modifications at the RNA level (termed “epitranscriptome”) have opened new possibilities for the pharmacological targeting of these modifications as an intervention strategy in human diseases with aberrant epitranscriptomes. Over the last 50 years more than 140 posttranslational modifications in RNA molecules have been identified (Boccaletto et al., 2018), most of them affecting the most abundant RNAs: ribosomal RNA (rRNA) andtransfer RNA (tRNA) (Roundtree et al., 2017a). However, it is only during the past decade have we started to construct the first maps of messenge r RNA (mRNA) modifications and to envision their impact on gene regulation.
The four RNA bases (A, T, C, U) as well as the ribose sugar can harbour modification sites that range from base isomerization processes to chemical modifications, including inosine (I), 5‑methyl cytidine (m5C; also known as 5mC), 5‑hydroxylmethyl cytidine (hm5C; also known as 5hmC), pseudo-uridine (Ψ), N6-methyladenosine (m6A) and N1-methyladenosine (m1A). Nowadays, we have identified and characterized mRNA posttranslational modifications that are known to be important for RNA biogenesis, RNA dynamism and RNA function under physiological conditions. In addition, their impact on the onset and progression of human diseases, especially cancer, has been recently examined. Despite all efforts, the field of epitranscriptomics is still in its infancy and we are still far from obtaining a complete landscape of RNA modifications and the molecular and biological pathways in which they are involved. What is clear from the latest evidences, however, is that RNA does not merely act as an effector molecule but it has an active role in the regulation of gene expression. In this review, we will describe the principal RNA modifications (with a focus on mRNA), summarize the latest scientific evidences of their dysregulation in cancer and provide an overview of the state-of-the-art drug discovery efforts. Finally, we will discuss the principal challenges in the field of chemical biology and drug development to increase the potential of targeted-RNA for clinical benefit.