Drug Discovery Initiative (DDI) celebrated its 10th anniversary of foundation last year. DDI, has been contributed as a hub of the national collaborative research network for drug discovery based on DDI’s public chemical library, consultation, technical assistance to the academia researchers who will begin chemical screening to identify hit compounds against drug discovery targets. In 2016, with the aim of enhancing the probability of innovative drug creation from academia, lead exploration unit, the University of Tokyo, was established as an internal organization of DDI. In the lead exploration unit, the University of Tokyo, hit-to-lead synthesis support will be conducted mainly by the active researchers from pharmaceutical companies, taking into account of ADME and physicochemical property evaluation, which was difficult to implement in the past in the academia.

Since vorinostat, a histone deacetylase (HDAC) inhibitor, was approved by FAD, expectations to epigenetic drug discovery have been increased. Recently, not only HDAC inhibitors but also histone methyltransferase inhibitors or lysine specific demethylase inhibitors have been tested in clinical trials. Therefore, novel epigenetic drugs may be approved as a therapeutic agent in the near future. Though epigenetic drugs used clinically so far have mainly pursued the development of anticancer agents, epigenetics is associated with various diseases such as central nervous system (CNS) disorders as well as cancer. In other words, there is also a need for the development of epigenetic drugs for other diseases. In this review, we present the outline of current epigenetic drug discovery and our medicinal chemistry studies on epigenetic drugs for CNS disorders.

Cortactin is an F-actin-binding protein that regulates cancer migration and invasion. The activity of cortactin is regulated by several posttranslational modifications including acetylation. Here, we identified Keap1, a negative regulator of the oxidative stress responsive transcriptional factor Nrf2, as a novel binding partner of cortactin, which regulates the cortactin activity. Furthermore, we found a molecular mechanism by which acetylation inhibits cortactin-mediated cell migration via interaction with Keap1. Our results suggest that SIRT2, identified as a cortactin deacetylase, is a potential target for cancer metastasis or invasion therapy. Therefore, we screened the chemical library for SIRT2 inhibitors, and succeeded in identifying several hit compounds. X-ray crystallographic analysis of the SIRT2-inhibitior complex revealed not only its unique mode of inhibition, but also existence of a regulatory mechanism of novel enzymatic activities of SIRT2.

By the based on sequence-specific DNA binding affinity of PI polyamides, we demonstrate the synthesis and evaluation of functional PI polyamides. The developments of functional PI polyamides could apply the enormous base sequence information obtained from the genome project as a drug. The strong expression restraint function that targeted various gene clusters for a human cell is expected by the covalent binding of DNA damage regulating PI polyamides. And, epigenetics regulating PI polyamides would apply activation of the specific gene expression as a kind of the artificial transcription factor in the future. Therefore, we explain on the possibility as the gene control technology of functional PI polyamides.

Zinc finger (ZF) proteins consist of Cys₂-His₂-type modules composed of approximately 30 amino acids that adopt a ββα structure and coordinate a zinc ion. ZF domains recognizing specific DNA target sequences can substitute for the binding domains of various DNA-modifying enzymes to create designer nucleases, recombinases, and methyltransferases with programmable sequence specificity. Enzymatic genome editing and modification can be applied to many fields of basic research and medicine. The recent development of new platforms using transcription activator-like effector (TALE) proteins or the CRISPR-Cas9 system has expanded the range of possibilities for genome-editing technologies. These technologies empower investigators with the ability to efficiently knockout or regulate the functions of genes of interest by using as sequence-specific nucleases. In addition, these DNA binding domains can also be utilized to build a tool box for epigenetic controls by fusing with protein modification enzymes or DNA modification enzymes. In this review, overview of recent advancements of sequence-specific DNA binding domains and their applications for genome and epigenome editing technologies is described. Our research for epigenome editing including development of artificial zinc finger recombinase (ZFR), split DNA methyltransferase utilizing ZF domains for target recognition, and fluorescent imaging of histone proteins by ZIP tag-probe system are introduced. Advances in the ZF, TALE, and CRISPR-Cas9 platforms have paved the way for the next generation of genome/epigenome engineering approaches. Perspectives for the future of epigenome engineering are also discussed, including development of precisely controlled epigenome editing and regulation.

Methylations of specific lysine residues of histone proteins are catalyzed by histone methyltransferases (HMTs), and play key roles in epigenetic control of gene expression. Recently, due to several reports of the links between each HMT and various diseases, HMTs have been regarded as a novel therapeutic target, so some practically useful inhibitors have been developed. One of HMTs, Set7/9, methylates Lys4 on histone protein H3, as well as non-histone proteins including estrogen receptor (ER) α. The methylation by Set7/9 stabilizes ERα, which is involved in the carcinogenesis of breast cancer, so its inhibitor could be a good and novel therapeutic agent. In this review, our recent research on the development of novel Set7/9 inhibitors based on coenzyme structure or cyproheptadine, which was originally a clinically approved antiallergy drug and very recently identified as a Set7/9 inhibitor, is summarized. And we also describe a convenient method to detect N-ε-monomethylation of lysine residue via a nucleophilic aromatic substitution reaction.

Histone acetylation is an important epigenetic modification that is involved in the regulation of many DNA-dependent cellular processes. BET bromodomain recognizes acetylated lysine in histones and influences transcriptional activity and chromatin remodeling, herein it has increasing attention as a target molecule for epigenetic therapy. Some BET inhibitors are already under clinical trials for the treatment of cancers. We have previously developed BRD4 inhibitors and BRD4/HDAC dual inhibitors. In this article, we will outline BET bromodomains as promising therapeutic targets and their current development status.

The gut microbiota forms a highly complex ecological community together with host intestinal cells. The so-called intestinal ecosystem has a profound influence on human physiology, immunology, and nutrition. It has been reported that imbalance in the structure of gut ecosystem could be a risk factor in human disorders including not only gut-associated disorders such as inflammatory bowel disease and colonic carcinogenesis, but also systemic diseases such as metabolic disorders and allergy. This review provides an overview of the importance of gut microbiota for our health and discusses the necessity of personalized healthcare based on the intestinal ecosystem.

The 11th Asian Federation for Medicinal Chemistry (AFMC) International Medicinal Chemistry Symposia (AIMECS17) was held in Melbourne, Australia from July 24 through 26, 2017. 9 invited lectures, 32 oral presentations and about 140 poster presentations were given. The symposium topics included “CADD”, “Epigenetics”, “Neglected Diseases” and so on. In this report, some lectures and outline of this symposium are reported.