The human epigenome plays a key role in determining cellular identity and eventually function. Drug discovery undertakings have focused mainly on the role of genomics in carcinogenesis, with the focus turning to the epigenome recently. Drugs targeting DNA and histone modifications are under development with some such as 5-azacytidine, decitabine, vorinostat, and panobinostat already approved by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA). This expert review offers a critical analysis of the epigenomics-guided drug discovery and development and the opportunities and challenges for the next decade. Importantly, the coupling of epigenetic editing techniques, such as clustered regularly interspersed short palindromic repeat (CRISPR)-CRISPR-associated protein-9 (Cas9) and APOBEC-coupled epigenetic sequencing (ACE-seq) with epigenetic drug screens, will allow the identification of small-molecule inhibitors or drugs able to reverse epigenetic changes responsible for many diseases. In addition, concrete and sustainable innovation in cancer treatment ought to integrate epigenome targeting drugs with classic therapies such as chemotherapy and immunotherapy.
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