Call for Papers: “Epigenetics 2.0”—A Joint Virtual Special Issue on Epigenetics

The term epigenetics was introduced in the early 1940s by the British biologist Conrad Waddington to define mechanisms by which an organism stably adapts its particular phenotype to the environment.¹ Since then, numerous research endeavors have been undertaken to investigate and understand the flexibility of the epigenome but also to develop small molecule inhibitors for epigenetic targets. Nowadays, all three families of epigenetic proteins—writers, erasers, and readers—have been modulated by small-molecule inhibitors (so-called epidrugs). In 2004, the DNA methyltransferase inhibitor azacytidine became the first epidrug to receive regulatory approval followed by the closely related analogue decitabine in 2006. The subsequent approvals of five histone deacetylase (HDAC) inhibitors (vorinostat, romidepsin, belinostat, panobinostat, and tucidinostat) and, most recently in 2020, the enhancer of zeste homologue 2 (EZH2) inhibitor tazemetostat underscore the vast potential of epidrugs for cancer therapy and, potentially, for nononcology indications.

Although there have been exciting developments in various fields of epigenetics, the failure of several epidrugs in clinical trials demonstrates that further research is needed to discover epidrugs with an improved benefit–risk profile and to identify biomarkers capable of predicting responsive patients. The field of epigenetics is located at the interface between medicinal chemistry, chemical biology, pharmacology, and translational science. Therefore, we are excited to host a joint virtual special issue in collaboration with ACS Chemical Biology, ACS Chemical Neuroscience, ACS Infectious Diseases, Journal of Medicinal Chemistry, and ACS Medicinal Chemistry Letters.

• ACS Chemical Biology invites submissions that use chemical biology approaches or devise chemical biology tools to understand or exploit epigenetic modifications.

• ACS Chemical Neuroscience will focus on epigenetic mechanisms associated with neurogenesis and neural plasticity as well as cognition and memory. Papers of interest also include those aimed at neuropsychiatric disorders for which epigenetic deregulation is a key driver of the disease phenotype.

• ACS Infectious Diseases encourages manuscripts that investigate epigenetic mechanisms that can offer some insights toward the development of infectious diseases, by affecting the survival, replication, or infection capacity of the pathogen or the response from the host.

• Journal of Medicinal Chemistry encourages submissions across the full spectrum of epigenetics, including epigenetic studies focused on human and nonhuman species.

• ACS Medicinal Chemistry Letters will focus on advances in our understanding of chemical modulators of chromatin and RNA modifications and accept manuscripts in the form of Notes, Letters, Innovations, and Technology Notes.

ACS Pharmacology & Translational Science will focus on recent advances in the field of epigenetics, including the development and recommendation of novel tool compounds for epigenetic targets and the discovery of new biomarkers. We highly invite active researchers to submit manuscripts to ACS Pharmacology & Translational Science for consideration for this special issue. Submissions of all manuscript types published in the journals are welcome. The following paragraphs describe some suitable topics for manuscripts in ACS Pharmacology & Translational Science.

Recommended Tool Compounds and New Modulators of Epigenetic Target Proteins

Over the past decades, numerous small molecule modulators of epigenetic regulator proteins have been discovered. However, gaining access to reliable information regarding which of the tool compounds available are best suited to address specific biological or pharmacological questions still remains an urgent need for several epigenetic target families. Especially medicinal chemists with an expertise in pharmacology, or interdisciplinary teams, are welcome to provide and summarize such highly useful information in review articles on specific epigenetic target proteins or target families. These types of articles should contain as much information on the tool compounds as available, including their suitability for cell-based or in vivo studies, data on pharmacokinetic parameters (e.g., solubility, membrane permeability, metabolic stability), recommended doses for particular experiments, etc. Ideally, the recommended epigenetic tool compounds should be commercially available or otherwise accessible. Biologists, pharmacologists, and translational scientists will highly appreciate this type of resource that aids in identifying and selecting the most suitable molecular tool compounds for their studies.² In addition to review articles, we would also like to encourage the submission of original research articles on the development of new small molecule modulators of epigenetic target proteins, in particular those that have potential for translation into diagnostics or therapeutic drugs.

Predictive Biomarkers and Resistance Mechanisms

The discovery of predictive genomic biomarkers and their clinical application during the development of molecular targeted therapies have proven to be of great value in the past. One example is the introduction of poly(ADP-ribose) polymerase (PARP) inhibitors in case of breast cancer gene (BRCA) mutations. However, until now very few predictive biomarkers have been identified for epidrugs. One of them is the SMARCA4 (SWI/SNF-related matrix-associated actin-dependent regulator of chromatin, subfamily A, member 4) genetic aberration, used for predicting the sensitivity to EZH2 inhibitors. Although there are some examples of favorable outcomes when using epidrugs for the treatment of hematological malignancies and other malignant diseases, some cases of resistance have also been reported. However, to date, the molecular mechanism underpinning these resistance mechanisms have not been explored extensively. Such studies would be very informative for further development of new epidrugs as well as for exploring novel combination therapies. There are preclinical reports of reverting the resistance of immune checkpoint inhibitors (e.g., cancer/testis antigen (CTA) expression) and modulating the adaptive immunity and tumor microenvironment (e.g., antigen presentation, infiltration of CD8+ T cells and T-cell exhaustion) upon the use of epidrugs. However, further validation and distinct biomarker identification are required to establish epidrugs in the clinical practice of immunotherapy. Therefore, we encourage the submission of original research articles and reviews dealing with the discovery of new predictive biomarkers and the elucidation of resistance mechanisms.

Summary

Manuscripts for this Virtual Special Issue must be received by December 31, 2021. Prospective authors are encouraged to use the presubmission inquiry mechanism to ensure relevance and appropriateness of research by contacting the Editorial Office: eic@ptsci.acs.org. For more information about the journal and manuscript types, please consult the Author Guidelines: https://pubs.acs.org/paragonplus/submission/aptsfn/aptsfn_authguide.pdf. Articles are placed into a regular journal issue after acceptance, instead of being published in a dedicated issue. Once all articles have been accepted, they will be collected on a single web page, giving additional exposure to each author’s work.

Views expressed in this editorial are those of the authors and not necessarily the views of the ACS.

Special Issue

Published as part of the ACS Pharmacology & Translational Science special issue “Epigenetics 2022”.