DOT1L

­­­­­Researchers have unraveled key physiological mechanisms to pave the way for the discovery of novel therapeutics XI'AN, China, March 23, 2023 /PRNewswire/ -- As the search for high-quality pharmaceutical drugs continues, researchers spend countless hours discovering the underlying mechanisms of drug action, thus expediting the drug discovery process. A recent example includes the discovery of the broad-spectrum anti-inflammatory effects of inosine, a nucleoside found in transfer RNAs, by researchers in China. These findings were made available online on 22 October 2022 and published in Volume 13, Issue 1 of Journal of Pharmaceutical Analysis (JPA) on 1st January 2023. Corresponding author, Yue Gao says, "Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced cytokine storms constitute the primary cause of COVID-19 progression, severity, criticality, and death. Glucocorticoid and anti-cytokine therapies are frequently administered to treat COVID-19 but have limited clinical efficacy in severe and critical cases." While attempting to develop effective treatment modalities for COVID-19, the researchers found that inosine downregulated the inflammation-promoting interleukin (IL)-6, upregulated the anti-inflammatory IL-10, and improved acute inflammatory lung injury. Their study suggests that inosine appreciably improved survival in mice infected with SARS-CoV-2 and hindered TANK-binding kinase 1 (TBK1) phosphorylation by binding stimulator of interferon genes and glycogen synthase kinase-3b. It also inhibited the activation and nuclear translocation of the downstream transcription factors, interferon regulatory factor and nuclear factor kappa B, and downregulated IL-6 in the sera and lung tissues of mice infected with lipopolysaccharide, H1N1, or SARS-CoV-2. Dr. Gao further adds, "Inosine is potentially an excellent broad-spectrum anti-inflammatory agent. Our study empirically demonstrated that inosine administration improved survival in severe SARS-CoV-2 infection through its immunomodulatory effects." The researchers concluded that inosine therapy may exert distinct anti-inflammatory effects in patients with severe COVID-19, and identified TBK1 as a promising target for inhibiting cytokine storms and for mitigating acute inflammatory lung injury. In another instance, Gu et al. demonstrated that compounds inhibiting disruptor of telomeric silencing-1-like (DOT1L) diminished the demethylation of histone H3 lysine 79 and inhibited the malignant behavior of uveal melanoma (UM) cells. This novel discovery can facilitate the development of the next generation of therapeutics targeting UM. As the author Xiang Gu, observes, "Our research reveals a novel targetable DOT1L-nicotinate phosphoribosyltransferase oncogenic mechanism, broadening the current understanding of UM therapies." Similarly, Li and colleagues identified squalene epoxidase as a promising therapeutic target for combating drug-induced hepatotoxicity. The author Zhiqi Li says, "We elucidate the hepatotoxicity mechanism of Paris polyphylla, commonly used in traditional herbal medicines, and provide a reference for its safe clinical use. These results may help to modify the structure of related chemical components responsible for the toxicity of polyphyllin 1, the active ingredient of Paris polyphylla, and make its clinical use safer by reducing its toxicity." In addition, Guo and co-authors demonstrated the promising antitumor efficacy of the supramolecular nanoreactor "DOC@TA-Fe3+" in a mouse model of colorectal cancer. The nanoreactor developed by the team rapidly accumulated at the tumor site following injection via the tail vein, attesting to its rapid transportability to the tumor tissue. Author Min Mu says, "The nanoreactor provides a new strategy for drug delivery and provides a reference for clinical research." Collectively, these cutting-edge studies pave the way for the identification of novel pathophysiological pathways, strongly boosting the process of drug discovery. Reference Title of original paper: Inosine: A broad-spectrum anti-inflammatory against SARS-CoV-2 infection-induced acute lung injury via suppressing TBK1 phosphorylation Journal: Journal of Pharmaceutical Analysis DOI: Contact: Mengjie Wang +86-29-82657423 355966@email4pr.com

Scientists have discovered only a handful of genes responsible for stem cell self-renewal, a property that allows stem cells to continue giving rise to a variety of cell types during an organism's lifespan. Now, a team has identified a new stem cell self-renewal factor, one essential for mice to produce sperm throughout their adult lives. Unlike women, who are born with all the eggs they'll ever have, men can continue to produce sperm throughout their adult lives. To do so, they require a constant renewal of spermatogonial stem cells, which give rise to sperm. This reinvigoration of stem cells depends on a newly characterized stem cell self-renewal factor called DOT1L, according to research by Jeremy Wang of the University of Pennsylvania School of Veterinary Medicine and colleagues. When mice lack DOT1L, the team showed, they fail to maintain spermatogonial stem cells, and thus, lack the ability to continuously produce sperm. Scientists have discovered only a handful of stem cell renewal factors, so the find, published in the journal Genes and Development, adds another entity to a rarified group. "This novel factor was only able to be identified by finding this unusual phenotype: the fact that mice lacking DOT1L were not able to continue to produce sperm," says Wang, the Ralph L. Brinster President's Distinguished Professor at Penn Vet and a corresponding author on the paper. "Identifying this essential factor not only helps us understand the biology of adult germline stem cells but could also allow us to one day reprogram somatic cells, like a type of skin cell called fibroblasts, to become germline stem cells, essentially creating a gamete in a petri dish. That is the next frontier for fertility treatment." The researchers happened upon DOT1L's role in stem cell self-renewal serendipitously. The gene is expressed widely; mice with a mutant version of DOT1L in all of their cells don't survive past the embryonic stage of development. But based on DOT1L's genetic expression patterns, Wang and colleagues believed that it could play a role in meiosis, the cell division process that gives rise to sperm and eggs. So, they decided to see what happened when they mutated the gene only in these germ cells. "When we did this, the animals lived and appeared healthy," Wang says. "When we looked closer, however, we found that the mice with the mutant DOT1L in their germ cells could complete an initial round of sperm production, but then the stem cells became exhausted and the mice lost all germ cells." This drop-off in sperm production could arise due to other problems. But various lines of evidence supported the link between DOT1L and a failure of stem cell self-renewal. In particular, the researchers found that the mice experienced a sequential loss of the various stages of sperm development, first failing to make spermatogonia and then spermatocytes, followed by round spermatids, and then elongated spermatids. In a further experiment, the researchers observed what happened when DOT1L was inactivated in germ cells not from birth, but during adulthood. As soon as Wang and colleagues triggered the DOT1L loss, they observed the same sequential loss of sperm development they had seen in the mice born without DOT1L in their germ cells. Previously, other scientific groups have studied DOT1L in the context of leukemia. Overexpression of the gene in the progenitors of blood cells can lead to the malignancy. From that line of investigation, it was known that DOT1L acts as a histone methyltransferase, an enzyme that adds a methyl group to histones to influence gene expression. To see whether the same mechanism was responsible for the results Wang and his team had observed in sperm development, the researchers treated spermatogonial stem cells with a chemical that blocks the methyltransferase activity of DOT1L. When they did so, the stem cells' ability to give rise to spermatogonia was significantly reduced. The treatment also impaired the ability of stem cells to tag histones with a methyl group. And when these treated stem cells were transplanted into otherwise healthy mice, the animals' spermatogonial stem cell activity was cut in half. The team found that DOT1L appeared to be regulating a gene family known as Hoxc, transcription factors that play significant roles in regulating the expression of a host of other genes. "We think that DOT1L promotes the expression of these Hoxc genes by methylating them," says Wang. "These transcription factors probably contribute to the stem cell self-renewal process. Finding out the details of that is a future direction for our work." A longer-term goal is using factors like DOT1L and others involved in germline stem cell self-renewal to help people who have fertility challenges. The concept is to create germ cells from the ground up. "That's the future of this field: in vitro gametogenesis," Wang says. "Reprogramming somatic cells to become spermatogonial stem cells is one of the steps. And then we'd have to figure out how to have those cells undergo meiosis. We're in the early stages of envisioning how to accomplish this multi-step process, but identifying this self-renewal factor brings us one step closer."

CAMBRIDGE, Mass., April 8, 2014 /PRNewswire/ -- Epizyme, Inc. (NASDAQ: EPZM), a clinical stage biopharmaceutical company creating innovative personalized therapeutics for patients with genetically defined cancers, announced today that the U.S. Patent and Trademark Office has granted U.S. Patent No. 8,691,507 with claims that cover the identification of patients carrying EZH2 oncogenic mutations as candidates for treatment with EZH2 inhibitors. EZH2 is a histone methyltransferase (HMT) that can become oncogenic due to genetic alterations and cause non-Hodgkin lymphoma and solid tumors. The patent, entitled "Inhibitors of Human EZH2 and Methods of Use Thereof," expires in 2033. "We believe the issued claims, which cover detecting the presence of an EZH2 mutation and treatment with an EZH2 inhibitor, are the first instance of patented diagnostic applications for EZH2 cancers," said Zoran Zdraveski Ph.D, J.D., Chief Patent Counsel, Epizyme. "These diagnostic and treatment claims complement our issued composition of matter claims that expire in 2032. Our growing patent estate reflects the potential of our product platform to create personalized therapeutics for patients with genetically defined cancers." Epizyme's small molecule inhibitor of EZH2, EPZ-6438 (E7438), is currently being developed in a Phase 1/2 clinical trial in patients with advanced solid tumors or relapsed or refractory B-cell lymphoma. In 2014, Epizyme plans to initiate two proof of concept studies with EPZ-6438 pending Phase 1 completion, one in non-Hodgkin lymphoma patients with EZH2 point mutations and one in synovial sarcoma patients. EPZ-6438 is being developed in collaboration with Eisai, Inc. About EZH2 Cancers EZH2 is a histone methyltransferase (HMT) that can become oncogenic due to genetic alterations and cause non-Hodgkin lymphoma and solid tumors. Oncogenic EZH2 mutations are associated with two types of non-Hodgkin lymphoma, diffuse large B-cell lymphoma of germinal-center origin, or DLBCL, and follicular lymphoma, or FL. Currently, there are no therapies approved specifically for the treatment of non-Hodgkin lymphoma associated with an EZH2 point mutation. About EPZ-6438 Epizyme and it's partner Eisai are developing EPZ-6438, a small molecule inhibitor of EZH2 created with our proprietary product platform, for the treatment of non-Hodgkin lymphoma patients who have an oncogenic (cancer-causing) point mutation in EZH2. In many human cancers, misregulated EZH2 enzyme activity results in misregulation of genes that control cell proliferation without these control mechanisms, cancer cells are free to grow rapidly. Epizyme granted Eisai a worldwide license to EPZ-6438 (Eisai refers to this therapeutic candidate as E7438), subject to Epizyme's right to opt in for co-development, co-commercialization and profit share arrangement with Eisai in the United States. Epizyme is working with Roche and Eisai to develop a companion diagnostic to identify patients with non-wild type EZH2, where EZH2 contains point mutations. Additional information about these partnerships may be found here: In June 2013, Epizyme and its partner Eisai initiated a Phase 1/2 clinical trial of EPZ-6438 in patients with advanced solid tumors or with relapsed or refractory B-cell lymphoma. This program is currently in the dose escalation phase. The company believes EPZ-6438 is the second HMTi to enter human clinical development (following Epizyme's DOT1L inhibitor, EPZ-5676). Additional information about this program, including clinical trial information, may be found here: About Epizyme, Inc. Epizyme, Inc. is a clinical stage biopharmaceutical company creating personalized therapeutics for patients with genetically defined cancers. Epizyme has built a proprietary product platform that the company uses to create small molecule inhibitors of a 96-member class of enzymes known as histone methyltransferases, or HMTs. HMTs are part of the system of gene regulation, referred to as epigenetics, that controls gene expression. Genetic alterations can result in changes to the activity of HMTs, making them oncogenic (cancer-causing). By focusing on the genetic drivers of cancers, Epizyme's targeted science seeks to match the right medicines with the right patients for a personalized approach to cancer treatment. For more information, visit and connect with us on Twitter at @EpizymeRx. Cautionary Note on Forward-Looking Statements Any statements in this press release about future expectations, plans and prospects for the Company, including statements about the Company's strategy, future operations, development of the Company's therapeutic candidates, and future expectations and plans and prospects for the Company and other statements containing the words "anticipate," "believe," "estimate," "expect," "intend," "may," "plan," "predict," "project," "target," "potential," "will," "would," "could," "should," "continue," and similar expressions, constitute forward-looking statements within the meaning of The Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by such forward-looking statements as a result of various important factors, including: whether the patents and patent applications owned or licensed by the Company, such as the patent referred to in this release, will protect the Company's technology and prevent others from infringing it, the uncertainties inherent in the initiation of future clinical trials, expectations of expanding ongoing clinical trials, availability and timing of data from ongoing clinical trials, expectations for regulatory approvals, development progress of the Company's companion diagnostics, availability of funding sufficient for the Company's foreseeable and unforeseeable operating expenses and capital expenditure requirements, other matters that could affect the availability or commercial potential of the Company's therapeutic candidates or companion diagnostics and other factors discussed in the "Risk Factors" section of the Company's Registration Statement on Form 10-K filed with the Securities and Exchange Commission on February 28, 2014. In addition, the forward-looking statements included in this press release represent the Company's views as of the date hereof. The Company anticipates that subsequent events and developments will cause the Company's views to change. However, while the Company may elect to update these forward-looking statements at some point in the future, the Company specifically disclaims any obligation to do so. These forward-looking statements should not be relied upon as representing the Company's views as of any date subsequent to the date hereof. SOURCE Epizyme, Inc. Help employers find you! Check out all the jobs and post your resume.