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."

July 9, 2015 By Mark Terry , BioSpace.com Breaking News Staff Cambridge, Mass.-based Epizyme, Inc. , announced today that it amended its agreement with Celgene Corporation for at least three more years. The original agreement, signed three years ago, was for EPZ-6438 (tazemetostat) for the treatment of non-Hodgkin lymphoma patients and patients with INI1-deficient solid tumors, and EPZ-5676 (pinometostat), an inhibitor of DOT1L for the treatment of patients with acute leukemia with a chromosome rearrangement in the MLL gene. There are three predefined targets for the two compounds. As part of the revised agreement, Epizyme will receive a $10 million extension fee in exchange for an option to individually license global rights to the two drugs, and worldwide rights except U.S. for a third target. Epizyme will handle development and funding through Phase I trials. After that, if it wants to, Celgene can continue to license for a specific target for additional fees that have already been agreed upon. All told, Epizyme could earn up to $620 million for all three targets. The breakdown is $10 million upfront, $75 million in developmental milestones and license fees, $365 million in regulatory milestones, and another $170 million in sales milestones. There is also the possibility of double-digit royalties for Epizyme. “We believe that the extension of our agreement with Celgene will accelerate our goal of developing new therapies that have the potential to help many patients with epigenetically driven cancers,” said Roberg Gould, president and chief executive officer of Epizyme in a statement. “Celgene is a leading company in oncology development and commercialization and we are pleased to continue our partnership on pinometostat and these three exciting novel targets.” Celgene , headquartered in Summit, N.J., recently signed a global collaboration agreement with Seattle-based Juno Therapeutics, Inc. That deal runs for ten years and involved an upfront payment to Juno of about $150 million. Celgene bought 9,137,672 shares of Juno’s common stock for $93 per share, or about $850 million. Under the agreement, Celgene has the chance to partner with Juno’s oncology and cell therapy auto-immune product candidates, which includes CD19 and CD22 directed CAR-T product candidates. A B-cell Maturation Antigen (BCMA) is not included in the deal. Juno will be responsible for North American research and development efforts and will hold commercialization rights in that territory. Celgene will handle development and commercialization for the rest of the world and pay royalties on any sales to Juno. That figure, $93 per share, seems pretty high when is currently trading for $49.10 per share. But that figure gives Celgene access to Juno’s pipeline along with almost $1 billion in working capital. Juno gets a 30 percent stake in some of Celgene’s compounds. Brian Orelli , writing in The Motley Fool, says the $93 figure is “meaningless.” The key, according to Orelli, is that Celgene gained 10 percent of Juno and “If Juno’s CAR-T technology works, $460 million will look like a steal.” The $460 million figure is based on calculations related to the current share prices and the company’s market cap of about $5.4 billion. He compared it to a recent deal between Eli Lilly and BioNTech . That deal started with a $30 million signing fee, then Lilly invested another $30 million equity investment in Cell & Gene Therapies GmbH, a subsidiary of BioNTech, which is headquartered in Mainz, Germany. The focus of that deal is also CAR T-cell immunotherapy, which is believed to have great potential for treating B cell cancers, or lymphomas. In addition to announcing the deal with Celgene, Epizyme gave a financial update, indicating it has enough cash to fund itself through at least the end of the second quarter of 2017. The company will push its development of tazemetostat, but reprioritize its pipeline development and cut operating cuts. In an email to FierceBiotech , Epizyme’s Andrew Singer , the chief financial officer, said, “No layoffs have been included or are contemplated.” As New Jersey Biotech Booms, Will It Overtake Other States As Prime Location? A week after Celgene Corporation announced it is officially the mystery buyer of Merck & Co. ’s former 1 million-square-foot R&D site in Summit, N.J., it quickly became our most popular story last week. The company announced last Wednesday that it is buying the space, ending months of speculation about what Big Pharma company might move into the neighborhood. The Summit, N.J. site is zoned research/office. The New Jersey site would put operations closer to some of the major biotech and pharmaceutical hubs on the East Coast. But, by far, the most tempting part of doing business in the state remains New Jersey’s operating tax credit, which allows companies to sell their net operating losses to the New Jersey Treasury. One of the state’s most recognizable biotechs, Celgene, used the program until it became profitable, which was key to it staying in the state, said local officials. That has BioSpace is wondering if New Jersey is becoming the new face of biotech . What do you think? Can the Garden State compete with other longtime stalwarts like California or Boston? var _polldaddy = [] || _polldaddy; _polldaddy.push( { type: "iframe", auto: "1", domain: "biospace.polldaddy.com/s/", id: "as-new-jersey-biotech-booms-will-it-overtake-other-states-as-prime-location", placeholder: "pd_1436372551" } ); (function(d,c,j){if(!document.getElementById(j)){var pd=d.createElement(c),s;pd.id=j;pd.src=(' '==document.location.protocol)?' ':' ';s=document.getElementsByTagName(c)[0];s.parentNode.insertBefore(pd,s);}}(document,'script','pd-embed'));