Daiichi Sankyo's EZHARMIA (Valemetostat, valmetostat) (DS-3201, DS-3201b) was recently approved in Japan for the treatment of refractory leukemia and lymphatic cancer, becoming the first dual inhibitor of EZH1/2 to receive regulatory approval.
Valmetostat, a first-class dual inhibitor of EZH1/2, has shown activity in both T-cell and B-cell lymphomas, making it a standout among lymphoma drugs, since the vast majority only treat one or the other. Clinical trials showed that valmetostat shrank tumors in 48% of patients, including 20% who had no signs of cancer after treatment.
In China, HH2835, a domestic drug targeting the same target, is also undergoing clinical trials in both China and the United States. This drug is a novel, highly effective and specific dual inhibitor of EZH1/2 jointly developed by Haihe Biology and Shanghai Institute of Materia Medica, Chinese Academy of Sciences. At present, it is the only EZH inhibitor applied for clinical research in China.EZH1 and EZH2, both histone methyltransferases, are major epigenetic regulators. Epigenetic drugs may sound unfamiliar, but they have been studied for more than 50 years.
What is epigenetics?
Epigenetics is a concept corresponding to genetics. Epigenetics is defined as "the regulatory code that determines the expression of genes and can be stably inherited without changing the genome sequence". Chromatin condensation, the formation of relaxed structures, and the transition between open and closed states provide a regulatory mechanism beyond the DNA sequence itself, namely epigenetic regulation.
Tumor cells usually use epigenetic regulatory mechanisms to activate oncogene expression programs. Unlike genetic changes, epigenetic changes are reversible and do not alter our DNA sequence, but they can alter the way our bodies read DNA sequences. Chromatin is one of the first cancer therapeutic targets identified. As early as the 1970s, scientists began to design differentiation drugs that alter chromatin in association with DNA methylation.
While compounds from different sources, including Chinese herbal medicines, food and beverages, exert beneficial health effects through mechanisms affecting the epigenome and gene expression during disease pathogenesis. By targeting so-called epigenetic "readers," "authors," and "erasers," chemicals can reverse abnormal epigenomic signatures in cancer cells and precancerous stages. Thus, such drugs provide avenues for cancer interception through either preventive or therapeutic/therapeutic strategies. Most previous studies have focused on writers (e.g., histone acetyltransferases) and erasers (e.g., histone deacetylases), with less attention paid to epigenetic readers (e.g., histone methyltransferases).
It was not until 2012 that the famous gene "switch molecule" JQ1 synthesized by Harvard scientist Jun Qi was developed as an epigenetic "reader" inhibitor, selectively targeting BET family member BRD4. Clinical trials using JQ1 as a single agent or in combination with standard of care therapy have shown antitumor efficacy, but concerns about toxicity or drug resistance require further development of next-generation drugs targeting epigenetic-related targets.
Epigenetic drug development strategies
Dr. Jun Qi recently published a review in the special issue of "Epigenetics 2022" of the Journal of Medicinal Chemistry, discussing various drug design strategies for epigenetic readers targeting histone methyltransferases (HMTs) in the past five years, including non-covalent inhibitors, covalent inhibitors, PROTACs inhibitors, etc. Abnormal expression of histone methyltransferases (HMTs) can lead to abnormal methylation of cancer-related genomic proteins, thereby promoting tumorigenesis. Histone methyltransferases are associated with chemotherapeutic resistance and immune stimulation, making these enzymes potential therapeutic targets, and small molecule targeting of these proteins provides avenues for the development of new drugs in cancer therapy.
Histone methyltransferases (HMTs) are classified into two groups: lysine methyltransferases (KMTs) and arginine methyltransferases (PRMTs). Dysregulation of KMTs has been linked to the causes of many diseases, including cancer, mental health disorders, and developmental disorders. KMTs can be divided into set-containing domains and non-SET domains. SET domain is an important domain of histone methyltransferases, which is responsible for the enzymatic activity of methyltransferases, including SUV39, SET1, SET2, EZH (EZH1 and EZH2 have been marketed), RIZ (PRDM, SMYD, SUV420) and other families. However, there are few proteins without SET domain, such as DOT1L protein. DOT1L is a histone methyltransferase known to target the histone H3K79 position. Over the past decade, significant progress has been made in developing drugs that target KMT involved in histone methylation and epigenetic regulation. The first of these inhibitors, tazemetostat, was approved in 2020 for the treatment of epithelioid sarcoma and follicular lymphoma and is currently in phase 3 clinical trials in China.
At present, nine species of PRMTs have been identified in mammals. According to their catalytic activities, they can be divided into three categories: monomethylation (MMA) of arginine, asymmetric methylation (ADMA) or symmetric dimethylation (SDMA) of arginine. Type I PRMTs (PRMT1, PRMT2, PRMT3, PRMT4, PRMT6, and PRMT8) produce mono-or asymmetric dimethylated arginine (ADMA), Type II PRMTs (PRMT5 and PRMT9) produce mono-or symmetrically dimethylated arginine (SDMA). Type Ⅲ PRMT7, however, produces only MMA. Due to the increasing importance of PRMT family members in various cancer types, the pipeline of new drugs has a number of selective inhibitors targeting PRMT family members. PRMT4, PRMT5, and PRMT7 have become increasingly promising therapeutic targets, as overexpression and dysregulation of these proteins have been reported to promote tumorigenesis in a range of solid and blood cancers. These enzymes could be used not only as targets for monotherapy, but also in combination strategies to overcome drug resistance and boost immune responses.
Multiple inhibitors targeting EZH2, DOT1L, and multiple PRMT family members have been successfully developed or are in clinical trials. For example, Epizyme's DOT1L inhibitor pinometostat (EPZ-5676) entered clinical trials, but its clinical activity was not high. G9A inhibitor EZM8266, PRMT5 inhibitor, etc.
Non-nucleoside DOT1L inhibitor DC_L11 was also reported by Shanghai University of Science and Technology in China. In order to overcome the deficiency of inhibitors, a number of PROTAC inhibitors targeting HMT have been reported recently: For example, a series of EZH2-specific ProTACs were developed by combining the CRBN binder thalidomide with EZH2 inhibitors GSK126 and EPZ6438 (Tazemetostat), which mimic the structure of SAM. Gsk126-based depressors were more capable of degrading EED and SUZ12 than EZH2 inhibitors, and in addition, complete degradation of EZH2 was shown to eliminate its oncogenic function, including reduced methylation, a feat not achieved by current EZH2 inhibitors.
conclusion
Small molecule inhibitors and depressants targeting HMT have shown great potential for cancer treatment, This is evidenced by the number of inhibitors entering the development stage of clinical trials, the continued advances in chemobiological approaches, and the increasing scientific interest in the role of HMT in disease that states and mediators of drug response will lead to further development and refinement of these compounds.
At the same time, advances and increased availability of high-throughput compound screening platforms have greatly expanded the range of potential HMT selective inhibitors that already exist. In addition, computational chemistry methods, including the use of crystal structures and molecular docking, have provided more tools for drug discovery.
Despite the exciting progress in HMT-targeted compound development, epigenetic modification probes as a whole still fall short in terms of the time required for compound effectiveness compared to kinase inhibitors and conventional chemotherapy. On the other hand, epigenetic treatment progress is still mainly focused on hematological tumors, and more work is needed for solid tumors.
The birth of epigenetics has been nearly 50 years, and the related research is getting deeper and deeper. Although some gaps in knowledge have been filled, more questions are emerging. Another challenge is that most epigenetic alterations are loss-of-function mutations, which are difficult to treat. Epigenetic drugs may work better in combination with classical chemotherapy, targeted drugs, other epigenetic drugs, and immune checkpoint inhibitors than they do alone.
In conclusion, epigenetically related proteins represent an important class of therapeutic targets. Considering the large number of potential targets, it is necessary to systematically discover and validate potential drug targets for drug development to achieve ideal efficacy.
