Epigenetics in Drug Discovery

Introduction & scope

• Epigenetics — heritable-yet-reversible changes in gene expression that do not alter the underlying DNA base sequence — mediated by DNA methylation, covalent histone modifications, chromatin (nucleosome) remodelling, and non-coding RNAs.
• Scope of this topic = epigenetics as a source of druggable targets and of approved drugs, plus pharmacoepigenomics — explicitly distinct from classical pharmacogenetics/pharmacogenomics (variation in germline DNA sequence).
• A rationally-invented target class — modern drugs are largely invented — "totally new compounds, painstakingly optimized against many criteria" — against a defined molecular target; chromatin-modifying enzymes are exactly this kind of rationally selected target.
• The reversibility advantage — because epigenetic marks are enzymatically written and erased (unlike a fixed mutation), they are in principle pharmacologically reversible targets — a small molecule can restore a dysregulated expression state rather than correct a genetic lesion.
• Cancer is the beach-head indication — somatic (tumour) genome variants are "a critical determinant of anticancer drug effects" and tumour sequencing to choose targeted agents "is becoming standard of care"; every first-generation approved epigenetic drug is an oncology drug, and the mutation-selective agents (IDH1/2, EZH2) follow the somatic-mutation-directed model used for EGFR/HER2/BRAF.