Epigenetics-targeted drugs: current paradigms and future challenges

Abstract

Epigenetics governs a chromatin state regulatory system through five key mechanisms: DNA modification, histone modification, RNA modification, chromatin remodeling, and non-coding RNA regulation. These mechanisms and their associated enzymes convey genetic information independently of DNA base sequences, playing essential roles in organismal development and homeostasis. Conversely, disruptions in epigenetic landscapes critically influence the pathogenesis of various human diseases. This understanding has laid a robust theoretical groundwork for developing drugs that target epigenetics-modifying enzymes in pathological conditions. Over the past two decades, a growing array of small molecule drugs targeting epigenetic enzymes such as DNA methyltransferase, histone deacetylase, isocitrate dehydrogenase, and enhancer of zeste homolog 2, have been thoroughly investigated and implemented as therapeutic options, particularly in oncology. Additionally, numerous epigenetics-targeted drugs are undergoing clinical trials, offering promising prospects for clinical benefits. This review delineates the roles of epigenetics in physiological and pathological contexts and underscores pioneering studies on the discovery and clinical implementation of epigenetics-targeted drugs. These include inhibitors, agonists, degraders, and multitarget agents, aiming to identify practical challenges and promising avenues for future research. Ultimately, this review aims to deepen the understanding of epigenetics-oriented therapeutic strategies and their further application in clinical settings.

Fig. 1

Epigenetic mechanisms and key examples of widely studied modifications and their modifying enzymes. a DNA modifications, histone modifications, RNA modifications, chromatin remodeling, and the regulation based on non-coding RNA constitute the core content of epigenetics, being responsible for passing on heritable variations of genetic information independently of the DNA sequence. b Epigenetic modifications are reversible progress catalyzed by functionally complementary modifying enzymes, which provide targets for disease therapeutics

Fig. 2

Timeline of major discoveries and advances in epigenetic research. The significant discoveries and advances are depicted in the illustrator and displayed as primarily “Early foundations” (yellow boxes) on the top, “Improving safety and efficacy” (purple boxes) in the middle, and “Breakthroughs in the clinical practice” (pink boxes) at the bottom

Fig. 3

Epigenetic mechanisms in cancer. Epigenetic alterations in cancer cells affect various cellular responses, such as cell proliferation, invasion, apoptosis, and drug resistance. These modifications, which include DNA modification, histone modification, RNA modification, chromatin remodeling, and non-coding RNAs, significantly affect the pathogenesis and progression of tumors. By targeting these epigenetic mechanisms, novel therapeutic strategies for combating cancer can be developed. The primary roles of epigenetic mechanisms in tumorigenesis and their further development are presented in the illustrator

Fig. 4

The development direction and major categories of epigenetics-targeted drugs. a Epigenetics-targeted drugs are developed through the virtual screening of compound libraries, drug design based on molecular structure, and the exploration of potential mechanisms of known agents. Subsequently, applying PROTAC, CRISPR/Cas, and other technologies or mechanisms to optimize the physical properties, and inhibitory or agonistic effects of compounds. Finally, the druggability of possible agents should be improved in experimental, preclinical and clinical studies. b The classification of epigenetics-targeted drugs and their corresponding marketed representative agents are depicted in this section. Among them, epigenetics-targeted drugs that have already been approved and applied in clinical treatment are highlighted in corresponding colors

Fig. 5

The promising trends and practical challenges in the clinical application of epigenetics-targeted drugs. From the perspective of clinical practice, epigenetic agents are expected to become promising adjuvants in combination with traditional antitumor therapeutics, contributing to superior efficacy and decreased resistance. Based on this idea, multitarget anticancer agents inhibiting both HDAC and other pathological molecules have gained much attention as a new strategy. Further, epigenetic degraders based on PROTAC or other techniques responsible for TPD help supplement the catalytic function of epigenetic inhibitors. Notably, the successful transport of epigenetic regulators to specific tissues or cells, or even the finite subcellular structures, is the prerequisite for exerting therapeutic effects. The further optimization of different types of nanoparticles makes them inspiring tools for the delivery system