DNAJB1

Researchers will apply the latest TPD drug discovery technology to target fusion proteins that cause pediatric cancer Cancer Grand Challenges is an initiative funded by Cancer Research UK SAN FRANCISCO, March 25, 2024 (GLOBE NEWSWIRE) -- Nurix Therapeutics, Inc. (Nasdaq: NRIX), a clinical stage biopharmaceutical company developing targeted protein modulation drugs designed to treat patients with cancer and inflammatory diseases, announced that it is part of a diverse research team of international experts selected as awardees in this year’s Cancer Grand Challenges competition. The team includes scientists, physicians and patient advocacy groups from 10 institutions in the United States, the United Kingdom, France, Germany and Austria and will be led by Yael Mossé, M.D., Professor of Pediatrics and Patricia Brophy Endowed Chair in Neuroblastoma Research at the Children’s Hospital of Philadelphia, and Martin Eilers, Ph.D., Professor of Biochemistry and Molecular Biology at the University of Würzburg, Germany. The project entitled “Knocking Out Oncogenic Drivers and Curing Childhood Cancers” (KOODAC) has the goal of developing orally bioavailable targeted protein degraders that have the potential to dramatically improve cure rates for children affected by solid tumors. In this first-of-its-kind industry/academic discovery partnership through Cancer Grand Challenges, Nurix will be making in-kind contributions to address each of the five onco-fusion targets, leveraging its DELigase technology to identify chemical starting points for drug design and providing key expertise in TPD optimization and development. "Team KOODAC brings together an interdisciplinary, international team of scientific experts, all sharing the vision of developing safe and effective drugs against previously undruggable childhood cancers," said Dr. Mossé. “We are excited to be working with Nurix, an industry leader in targeted protein degradation.” “We are proud to be invited to contribute our expertise in protein degradation to this impressive team consisting of some of the world's leading experts in pediatric cancers, oncoprotein biology, and protein degradation,” said Gwenn M. Hansen, Ph.D., chief scientific officer at Nurix. “Being chosen to be a part of this consortium and receiving this Cancer Grand Challenges recognition is a testament to the power, potential and leadership of Nurix’s targeted protein degradation technology to effectively target oncogenic fusion proteins that, until now, have been considered undruggable.” Team KOODAC will focus on the development of TPDs and Molecular Glue Degraders (MGDs) to target five key and previously undruggable fusion proteins that have been shown to be drivers of high-risk solid tumors in pediatric patients, including, MYCN, EWSR1-FLI, DNAJB1-PRKACA, ALK, and PAX3/7-FOXO1, and conduct the preclinical studies needed for biomarker-driven clinical trials. The Cancer Grand Challenges is an initiative driven and funded by Cancer Research UK, whose goal is to facilitate identification of the greatest challenges in cancer today and to fund global teams to work in innovative ways to find solutions. This year, five teams were selected to receive funding of up to £20 million (approximately $25 million) over a period of five years. The funds, which will support only the academic groups involved in the project, will be managed by Team KOODAC. About Nurix Therapeutics, Inc.Nurix Therapeutics is a clinical stage biopharmaceutical company focused on the discovery, development and commercialization of innovative small molecules and antibody therapies based on the modulation of cellular protein levels as a novel treatment approach for cancer, inflammatory conditions, and other challenging diseases. Leveraging extensive expertise in E3 ligases together with proprietary DNA-encoded libraries, Nurix has built DELigase, an integrated discovery platform, to identify and advance novel drug candidates targeting E3 ligases, a broad class of enzymes that can modulate proteins within the cell. Nurix’s drug discovery approach is to either harness or inhibit the natural function of E3 ligases within the ubiquitin-proteasome system to selectively decrease or increase cellular protein levels. Nurix’s wholly owned, clinical stage pipeline includes targeted protein degraders of Bruton’s tyrosine kinase, a B-cell signaling protein, and inhibitors of Casitas B-lineage lymphoma proto-oncogene B, an E3 ligase that regulates activation of multiple immune cell types including T cell and NK cells. Nurix is headquartered in San Francisco, California. For additional information visit http://www.nurixtx.com. Forward-Looking StatementsThis press release contains statements that relate to future events and expectations and as such constitute forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. When or if used in this press release, the words “anticipate,” “believe,” “could,” “estimate,” “expect,” “intend,” “may,” “outlook,” “plan,” “predict,” “should,” “will,” and similar expressions and their variants, as they relate to Nurix, may identify forward-looking statements. All statements that reflect Nurix’s expectations, assumptions or projections about the future, other than statements of historical fact, are forward-looking statements, including, without limitation, statements regarding: Nurix’s plans with respect to the KOODAC project the potential of Nurix’s targeted protein degradation technology to target oncogenic fusion proteins; the extent to which targeted protein degraders may address a range of diseases; and the potential advantages of Nurix’s scientific approach and DELigase™ platform. Forward-looking statements reflect Nurix’s current beliefs, expectations, and assumptions. Although Nurix believes the expectations and assumptions reflected in such forward-looking statements are reasonable, Nurix can give no assurance that they will prove to be correct. Forward-looking statements are not guarantees of future performance and are subject to risks, uncertainties and changes in circumstances that are difficult to predict, which could cause Nurix’s actual activities and results to differ materially from those expressed in any forward-looking statement. Such risks and uncertainties include, but are not limited to: (i) the risks inherent in the drug development process, including the unexpected emergence of adverse events or other undesirable side effects during clinical development; (ii) uncertainties related to the timing and results of clinical trials; (iv) whether Nurix will be able to fund its research and development activities and achieve its research and development goals; (v) the impact of economic and market conditions and global and regional events on Nurix’s business, clinical trials, financial condition, liquidity and results of operations; (vi) whether Nurix will be able to protect intellectual property and (vii) other risks and uncertainties described under the heading “Risk Factors” in Nurix’s Annual Report on Form 10-K for the fiscal year ended November 30, 2023, and other SEC filings. Accordingly, readers are cautioned not to place undue reliance on these forward-looking statements. The statements in this press release speak only as of the date of this press release, even if subsequently made available by Nurix on its website or otherwise. Nurix disclaims any intention or obligation to update publicly any forward-looking statements, whether in response to new information, future events, or otherwise, except as required by applicable law. Contacts: InvestorsJason Kantor, Ph.D.Nurix Therapeuticsir@nurixtx.com Elizabeth Wolffe, Ph.D.Wheelhouse Life Science Advisorslwolffe@wheelhouselsa.com MediaAljanae ReynoldsWheelhouse Life Science Advisorsareynolds@wheelhouselsa.com

Researchers have translated a cutting-edge tactic for treating genetic disorders into a fresh approach for potentially stymying cancer. Cell division is the generative spark of nearly every lifeform on Earth. But if healthy growth goes unchecked, cell division can turn lethal, overwhelming the organism. Such is the case with so-called oncogenes. When altered by a mutation, these growth-moderating genes go haywire, producing a geyser of cancer cells as a result. Oncogenes are also insidiously adept at generating tumors that over time become genetically "independent" from their origin, so it has been exceedingly difficult for scientists to shut down their replication at the source. Now Rockefeller University researchers have discovered a new way to target the oncogene behind a rare and often deadly liver disease using small interfering RNAs (siRNAs), an innate mechanism for silencing gene expression. As described in Molecular Therapy, the researchers slipped siRNAs inside fibrolamellar hepatocellular carcinoma (FLC) cells through a surface receptor, where they blocked the oncogene from producing illness-inducing proteins that lead to tumor formation. It's the first time that siRNAs have been used to hobble the progression of FLC, says first author Christoph Neumayer, a Ph.D. student in Rockefeller's Laboratory of Cellular Biophysics, headed by Sanford M. Simon. But the findings have wider applications as well. "That's the really exciting part," says Neumayer. "This is proof of concept that siRNAs can be used for FLC, as well as adult liver cancers, which are much more common, and other tumor types elsewhere in the body." The fusion oncogene FLC is caused by the fusion of two genes located on chromosome 19: DNAJB1, which produces heat-shock proteins that encourage cell homeostasis, and PRKACA, which produces an enzyme called kinase A that's key to cellular metabolic function. The resulting fusion, known as DNAJB1::PRKACA, brings together the proteins and a catalytic subunit of the kinase. This dysfunctional union promotes FLC formation, but how, exactly, is still unknown. Researchers in Simon's lab discovered that this fusion caused FLC in 2014, several years after Simon's own teenage daughter, Elana, was diagnosed with liver disease. After having the resulting tumor removed -- the only treatment option available to people with FLC -- Elana went on to collaborate with her father to unearth its cause, publishing the results in Science. Since then, Simon and his group have continued to reveal the mechanisms behind the disease as well as develop therapeutics. The siRNA research is part of a three-part strategy which also includes repurposing drugs for treating FLC and using molecules known as PROTACs to selectively degrade the DNAJB1::PRKACA protein that drives FLC. The drug repurposing is in advanced preparation for a clinical trial, and some of the PROTAC work is part of an international collaboration that was just awarded a $25 million Cancer Grand Challenges grant to develop treatments for high-risk, oncogene-driven cancers in children. Recently, Simon's lab discovered that they could completely stop FLC tumor growth in mice using shRNAs, short sequences of RNA that can be engineered to disrupt mRNA. The approach also caused many tumors to shrink or disappear. Having shown that quelling the fused oncogene killed tumor cells, they decided to experiment with derailing kinase A activity, which research indicated was driving tumor growth. Unlocking the cell door The problem was, fused kinase A and its "wild type" form are nearly identical, so "any drug you developed that blocks fused kinase A activity would affect all kinase A, including in normal cells," Neumayer says. "In other words, you would incur a host of problematic side effects." They had to find a way to disable toxic kinase while containing the impact so that kinase in other cells weren't affected. To do that, they specifically designed siRNAs to aim at the fusion. But because siRNAs cannot cross cell membranes, the researchers needed to figure out a way to get the siRNA inside. Luckily, a door into the cell had already been identified: a receptor called ASGR1 that's only expressed in liver cells. Its key had been too: a binding molecule known as GalNAc. Together, the duo function as a waste disposal team. GalNAc conjugate therapies, which attach siRNA molecules to the ligand to deliver therapies inside cells, are already on the market for conditions such as hereditary transthyretin-mediated amyloidosis and atherosclerotic cardiovascular disease. The team wondered if they could use the same approach to thwart the kinase driving FLC tumors. Stabilization and shrinkage To test their theory, the researchers attached a custom siRNA to the receptor's ligand and studied the method in a variety of tumor models in mice and in human cell cultures. The conjugate therapy was not only successfully delivered into the cells in all contexts, but it also caused a reduction of mRNA in the oncogene, preventing the production of the protein and resulting in the tumors stagnating or shrinking, unable to grow. They also did not detect any liver toxicity in the mice, indicating the animals tolerated the siRNAs well. "What we saw was tumor inhibition, when we had hoped to outright kill the tumor," Neumayer notes. "Our future direction will be to try to figure out how to improve that." They also tested the specificity of the siRNA by injecting it into tumor cells of another type of liver cancer. It had no toxic impact on them -- exactly as the researchers hoped. "We wanted to show that our siRNA is so targeted to the FLC fusion oncogene that it has no side effects on other cells -- even on other cancer cells," he notes. Neumayer says the findings suggest that siRNAs may be effective beyond FLC, capable of treating tumors throughout the body with a high degree of specificity: "I think siRNA medicines as a class will have a big impact over time as a new kind of genetic therapy."

A team deciphers complicated mechanism underlying genetic diversity. Movies such as 'X-Men,' 'Fantastic Four,' and 'The Guardians,' which showcase vibrant mutant heroes, have captivated global audiences. Recently, a high-throughput genetic screening of meiotic crossover rate mutants in Arabidopsis thaliana garnered the interest of the academic community by unraveling a century-old mystery in the life sciences. A research team, consisting of Professor Kyuha Choi, Dr. Jaeil Kim, and PhD candidate Heejin Kim from the Department of Life Sciences at Pohang University of Science and Technology (POSTECH), has achieved a remarkable feat by unveiling the molecular mechanism responsible for crossover interference during meiosis, a biological pattern at the chromosome level. The findings of this research were published on February 20 in Nature Plants, an international journal in the field of life sciences. In sexually reproducing organisms, individuals resemble their parents or siblings. Despite the striking similarities, it's crucial to recognize that absolute identicalness is unattainable. This variation is attributed to the process of meiosis, which generates reproductive cells like sperm and eggs in animals or pollen and ovules in plants. Unlike somatic cell division, which duplicates and divides the genome identically, meiosis creates genetically diverse reproductive cells through a mechanism known as crossover. Meiosis and crossover play pivotal roles in biodiversity and have significant implications in breeding where the selection and cultivation of superior traits in crops occur. Typically, most animal and plant species exhibit a minimum of one and a maximum of three crossovers per a pair of homologous chromosomes. The ability to control the number of these crossovers could lead to cultivating crops with specific desired traits. However, achieving such control has been challenging due to the 'phenomenon of crossover interference.' Crossover interference, where one crossover inhibits the formation of another crossover nearby along the same chromosome, was initially identified by fruit fly geneticist Hermann J. Muller in 1916. Despite researchers' persistent efforts over the past century since its discovery, it is only recently that the mechanisms underlying crossover interference have started to unveil their secrets. In this research, the team utilized a high-throughput fluorescent seed scoring method to directly measure crossover frequency in Arabidopsis plants. Through a genetic screen, they identified a mutant named hcr3 (high crossover rate3) that exhibited an increased crossover rate at the genomic level. Further analysis revealed that the elevated crossovers in hcr3 was attributed to a point mutation in the J3 gene, which encodes a co-chaperone related to HSP40 protein. This research demonstrated that a network involving HCR3/J3/HSP40 co-chaperone and the chaperone HSP70 controls crossover interference and localization by facilitating the degradation of the pro-crossover protein, HEI10 ubiquitin E3 ligase. The application of genetic screen approaches to uncover the crossover interference and inhibition pathway successfully addressed a century-old puzzle in the life sciences. POSTECH Professor Kyuha Choi stated, "Applying this research to agriculture will enable us to rapidly accumulate beneficial traits, thereby reducing breeding time." He expressed optimism by saying, "We hope this research will contribute to the breeding of new varieties and identification of useful natural variations responsible for desirable traits such as disease and environmental stress resistance, improved productivity, and high-value production." The research was conducted with support from the Basic Research Program in Science and Engineering and the Mid-Career Researcher Program of the National Research Foundation of Korea, the Next-Generation BioGreen 21 Program of the Rural Development Administration, the Suh Kyungbae Foundation, and the Samsung Science & Technology Foundation.