Epigenetics refers broadly to heritable changes in gene expression that arise from mechanisms other than changes in an organism’s or a cell’s DNA sequence. At the molecular level this occurs through specific covalent modifications to the nucleic acids and proteins comprising chromatin, thereby altering chromatin structure to regulate gene expression programs. In 2015 the Royal Society of Chemistry published Epigenetics for Drug Discovery, edited by Nessa Carey, providing a primer on the basics of the readers, writers and erasers of epigenetic chromatin covalent ‘marks’, and an overview of the drug discovery efforts and concepts at the time. Here we present an update to the field reflecting the tremendous progress over the past 10 years, the highlight of which is the approval of the first protein methyltransferase inhibitor, tazemetostat, for treatment of epithelioid sarcoma. Chapter 1 provides an historical perspective of the field while Chapters 2–6 discuss key and emerging technological advances to discover and evaluate epigenetic drugs and tool compounds, including safety considerations. Chapters 7–14 summarize the exciting progress and state of play for each of the major reader, writer and eraser target classes.

Subsequent chapters reflect how our understanding of epigenetic mechanisms in disease has greatly matured. For example, cancer genome sequencing projects continue to reveal a vast number of epigenetic regulators that are genetically mutated in cancers. Genetic mutations of epigenetic regulators are now recognized as a hallmark of human cancer, and we are now truly on a precision-focused cancer epigenetic drug discovery path. To help in this endeavour, many high-quality chemical probes are now available for epigenetic targets to better understand biological mechanisms and to evaluate the best target within a given disease model. Emerging biological insight into epigenetic mechanisms from studies in development and cell fate control is leading to recognition of epigenetic therapeutic mechanisms beyond simply up- or down-regulated transcriptional modulation. This increasing molecular complexity opens up new areas of research, such as control of the tumour micro-environment, cellular plasticity and therapy resistance mechanisms. Accordingly, the breadth of epigenetics as a field now includes chromatin remodelling complexes, RNA modifying enzymes (epitranscriptomics) and even directly drugging RNA as reflected in Chapters 15–17, respectively.

In addition to the success of tazemetostat, an ever-increasing number of novel agents targeting a variety of epigenetic target classes are showing promise in clinical trials. In this the second volume, it is therefore timely that we include three chapters to more deeply examine specific case studies to understand what drives success as well as the challenges in developing epigenetic therapies (Chapters 18–20). We hope this book conveys our optimism for the future with the increasing sophistication of epigenetic therapeutics in development, including allosteric inhibitors, many antagonists of protein–protein interactions and the rapidly evolving field of targeted protein degradation. These exciting modalities and the remarkable variety of epigenetic chemical probes and tool compounds are enabling ever more sophisticated studies to uniquely drug epigenetic targets in disease-specific settings.

We are grateful to the scientists from academia and industry who have contributed their time, expertise and wisdom in the 20 chapters of this volume, as well as the editors at the Royal Society of Chemistry, and to our colleagues who contributed to editing and proof reading: David Nie, Suzanne Ackloo, Manisha Yadav, Tristan Kenney, Maria Kutera, Jingwen Zhang, Michelle Lamb, Jon Read, John Reicha, Sungmi Park-Chouinard, Jay Mettetal and Meizhong Jin.

Ho Man Chan and Cheryl H. Arrowsmith