DNMT1

License provides exclusive access to innovative epigenetic editors and expands the reach of Chroma's platform BOSTON, June 27, 2024 /PRNewswire/ -- Chroma Medicine, Inc. (Chroma) a genomic medicine company pioneering single-course epigenetic editing therapeutics, today announced it has entered into an exclusive license agreement with the Whitehead Institute to access intellectual property and technology developed in the lab of Chroma co-founder Jonathan Weissman, Ph.D. The novel technology called CHARM (coupled histone tail for autoinhibition release of methyltransferase) uses a compact epigenetic editing effector domain to recruit and activate endogenous DNA methyltransferases to durably silence target genes. CHARM can utilize a self-silencing mechanism to limit its duration of expression and has been shown by Dr. Weissman's lab to induce brain-wide prion protein silencing in vivo. With an aim to deliver on the transformative potential of epigenetic editing, Chroma is expanding the versatility of its platform by leveraging this new technology to rapidly advance a new class of therapeutics that harness epigenetics, nature's innate mechanism for gene regulation, to achieve unparalleled control of gene expression without cutting, nicking, or altering the DNA sequence. "This agreement is a powerful example of our deep commitment to innovation in genomic medicines," said Catherine Stehman-Breen, M.D., Chroma's Chief Executive Officer. "Adding CHARM to our arsenal of technologies strengthens our mission to bring a broad portfolio of durable epigenetic editing therapeutics to patients." About Whitehead Institute and Weissman Laboratory Whitehead Institute is a world-renowned non-profit research institute dedicated to improving human health through basic biomedical research. Whitehead Institute's mission is to forge new frontiers in science, uncovering insights today that unlock the potential of tomorrow. The Weissman Laboratory is looking at how cells ensure that proteins fold into their correct shape, as well as the role of protein misfolding in disease and normal physiology. They are also developing experimental and analytical approaches for exploring the organizational principles of biological systems and globally monitoring protein translation through ribosome profiling. About Chroma Medicine Chroma Medicine is a biotechnology company pioneering a new class of genomic medicines that harness epigenetics, nature's innate mechanism for gene regulation, to deliver precise, programmable single-course therapeutics while preserving genomic integrity. The company's modular platform enables development of medicines that can address a wide range of complex diseases, whether they require silencing, activation, or targeting multiple genes at once. Chroma was founded by the world's foremost experts in genomic research and is led by a veteran team of industry leaders and scientists with deep experience in genomic medicine, drug discovery, and development. For more information, please visit chromamedicine.com or follow us on LinkedIn and X (formerly known as Twitter). SOURCE Chroma Medicine

Bacteria possess unique traits with great potential for benefiting society. However, current genetic engineering methods to harness these advantages are limited to a small fraction of bacterial species. A team has now introduced a novel approach that can make many more bacteria amenable to genetic engineering. Their method, called IMPRINT, uses cell-free systems to enhance DNA transformation across various bacterial strains. Bacteria possess unique traits with great potential for benefiting society. However, current genetic engineering methods to harness these advantages are limited to a small fraction of bacterial species. A team led by the Helmholtz Institute for RNA-based Infection Research (HIRI) in Würzburg has now introduced a novel approach that can make many more bacteria amenable to genetic engineering. Their method, called IMPRINT, uses cell-free systems to enhance DNA transformation across various bacterial strains. The findings were published today in the journal Molecular Cell. Bacteria populate virtually every habitat on Earth, including within and on our own bodies. Understanding and engineering bacteria can lead to new methods for diagnosing, treating, and preventing infections. Additionally, it presents opportunities to protect crops from disease and create sustainable cell factories for chemical production, reducing environmental impact -- just a few of the many benefits to society. To unlock these advantages, scientists need the ability to manipulate the genetic content of these bacteria. However, a longstanding bottleneck in genetically engineering bacteria has been the efficient transformation of DNA, the process of introducing foreign DNA into a cell. This has limited its application to only a small subset of microbes. A major obstacle is the presence of restriction-modification systems. These protective systems mark the bacterial genome with a unique methylation pattern and destroy incoming foreign DNA lacking this pattern. Overcoming this barrier requires adding the bacterium's pattern to the DNA, a process that is strain-specific and involves multiple DNA methyltransferases. These enzymes attach methyl groups, small chemical groups containing one carbon atom bonded to three hydrogen atoms, to DNA bases. Current methods to replicate or circumvent these DNA methylation patterns are labor-intensive and not easily scalable, necessitating new approaches. Addressing this challenge, a team led by the Helmholtz Institute for RNA-based Infection Research (HIRI), a site of the Braunschweig Helmholtz Centre for Infection Research (HZI) in cooperation with the Julius-Maximilians-Universität Würzburg (JMU), has introduced a novel approach to recreate such patterns and enhance DNA transformation. They called it IMPRINT, which stands for Imitating Methylation Patterns Rapidly IN TXTL. As part of this method, the researchers use a cell-free transcription-translation (TXTL) system -- a liquid mixture that can produce ribonucleic acids (RNAs) and proteins from added DNA -- to express a bacterium's specific set of DNA methyltransferases. The enzymes are then used to methylate DNA prior to its delivery into the target bacterium. A wholly new application "IMPRINT represents an entirely new use of TXTL. While TXTL is widely employed for various purposes, including producing hard-to-express proteins or as affordable diagnostic tools, it has not previously been utilized to overcome barriers to DNA transformation in bacteria," says Chase Beisel, head of the RNA Synthetic Biology department at the HIRI and professor at the JMU Medical Faculty. He spearheaded the study in collaboration with researchers from North Carolina State University (NC State) in Raleigh, USA. Their findings were published today in the journal Molecular Cell. Compared to existing methods, IMPRINT offers speed and simplicity: "Current approaches require either laboriously purifying individual DNA methyltransferases or expressing them in E. coli, which often proves cytotoxic," says Justin M. Vento, first author of the study who completed the work as a PhD student in the Department of Chemical and Biomolecular Engineering at NC State. "These methods can take days to weeks and only reconstitute a fraction of the bacterium's methylation pattern." The researchers demonstrated that IMPRINT could express a diverse array of DNA methyltransferases. Furthermore, these enzymes could be combined to recreate complex methylation patterns. This greatly enhanced DNA transformation in bacteria such as the pathogen Salmonella and the probiotic Bifidobacteria, including a challenging-to-transform strain of the latter, less-studied bacterium. The basis for new antibiotics and cell-based therapies The potential applications in modern medicine and research are extensive: IMPRINT can improve DNA transformation in clinical isolates of bacterial pathogens and in bacteria that combat infections, such as commensal bacteria or those producing antibacterial compounds. Genetic modification of these microbes could lead to new classes of antibiotics and cell-based therapies. The research team aims to expand the use of IMPRINT: "We want to make a wide variety of bacterial pathogens genetically tractable for research," Beisel says. He hopes that IMPRINT will be widely adopted by the research community: "Until now, certain bacteria have been favored as models simply because they are easier to genetically manipulate. We are hopeful that, by using IMPRINT, researchers will be able to focus on the most important bacterial strains, such as those with increased virulence or antibiotic resistance," Beisel concludes. The study was supported through funding by the US National Science Foundation, the German Research Foundation, the Novo Nordisk Foundation, the Camille and Henry Dreyfus Foundation, and the Bavarian State Ministry for Science and the Arts through the research network bayresq.net.

ROCKVILLE, Md. and SUZHOU, China, April 7, 2024 /PRNewswire/ -- Ascentage Pharma (6855.HK), a global biopharmaceutical company engaged in developing novel therapies for cancer, age-related diseases, and chronic hepatitis B (CHB), announced today that it releases the latest results from three preclinical studies of its novel drug candidates olverembatinib, MDM2-p53 inhibitor alrizomadlin (R&D Code: APG-115), FAK/ALK/ROS1 tyrosine kinase inhibitor APG-2449, and embryonic ectoderm development (EED) inhibitor APG-5918, at the 2024 American Association of Cancer Research Annual Meeting (AACR 2024). This year's AACR annual meeting will be held from April 5-10 2024, in San Diego, California, USA. "We are pleased to present the preclinical research data of four assets in our pipeline at the AACR 2024. The results provided essential support for the potential clinical development and therapeutic combinations of these compounds in SDH-deficient neoplasms, prostate cancer, and ovarian cancer," said Dr. Yifan Zhai, Chief Medical Officer of Ascentage Pharma. "Moving forward, we will continue to advance these programs toward the clinical stage in order to bring more treatment options to patients in need." The details of these three preclinical studies are as follows: Olverembatinib, a novel multikinase inhibitor, demonstrates superior antitumor activity in succinate dehydrogenase (SDH)-deficient neoplasms Abstract#: 1971 Time: Monday April 8, 2024, 9:00 AM - 12:30 PM (Pacific Time) Introduction: Succinate dehydrogenase (SDH) – deficient (dSDH) neoplasms are identified by the loss of immunohistochemical expression of SDHB due to the bi-allelic inactivation of any of the four components of mitochondrial SDH complex (SDH A-D). Succinate accumulation, due to SDH deficiency, is involved in tumorigenesis of different types of cancers including gastrointestinal stromal tumor (GIST), paraganglioma, pheochromocytoma, renal cell carcinoma, pituitary adenomas, and pancreatic neuroendocrine tumors. The prognosis of patients with dSDH neoplasia, especially GIST, is poor and approved tyrosine kinase inhibitors (TKIs) have limited efficacy. There is a high unmet medical need for these patients. Olverembatinib, a novel multi-kinase inhibitor, targets a broad spectrum of kinases and has demonstrated promising efficacy in dSDH GIST patients in an ongoing phase I clinical trial. In this study, we assessed antitumor effects of olverembatinib in preclinical models of dSDH cancers and dSDH GIST primary tumor cells, and explored potential mechanisms of action. Conclusions: Olverembatinib showed superior anti-tumor activity in dSDH cell lines in vitro and human dSDH GIST primary tumor cells ex vivo. Olverembatinib, as a multi-target kinase inhibitor, exerted antitumor effects by modulating multiple signaling pathways including hypoxia, angiogenesis, apoptosis, proliferation, and survival, which are involved in tumorigenesis of dSDH cancers. Olverembatinib demonstrated more potent in vivo antitumor activity in mice bearing PC12#5F7 (SDHB KD) xenograft tumors than other TKIs. Western blot analysis in tumor tissues collected from mice further confirmed the modulation of the signal pathways by olverembatinib observed in cell lines. In summary, the results provide a rationale for future clinical development of olverembatinib in dSDH cancers. Embryonic ectoderm development (EED) inhibitor APG-5918 (EEDi-5273) and MDM2 inhibitor alrizomadlin (APG-115) synergistically inhibit tumor growth in preclinical models of prostate cancer (PCa) Abstract#: 3223 Time: Monday April 8, 2024, 1:30 PM - 5:00 PM (Pacific Time) Introduction: Prostate cancer (PCa) is one of the most frequently diagnosed malignancies among elderly males. Androgen deprivation therapy (ADT) with or without androgen receptor (AR) inhibitors is widely used as initial treatment for advanced PCa. However, most ADT-treated patients eventually develop castration-resistant prostate cancer (CRPC), which is in urgent need of novel therapies. Polycomb repressive complexes 2 (PRC2) dysregulation is common in PCa and correlates with poor prognosis. PRC2 mediates histone H3 lysine 27 tri-methylation (H3K27me3), a repressive epigenetic marker for gene transcription. embryonic ectoderm development (EED), a PRC2 core component, is crucial for histone methyltransferase activity through direct binding to H3K27me3. MDM2, a negative regulator of the tumor suppressor p53, is frequently amplified or overexpressed in PCa, and associated with poor clinical outcomes and metastasis. The aim of this study was to evaluate antitumor activity and molecular mechanisms of the investigational, clinical-stage EED inhibitor APG-5918/EEDi-5273 and MDM2 selective inhibitor alrizomadlin (APG-115) in PCa preclinical models Conclusions: In PCa preclinical models, the combination of APG-5918 and alrizomadlin synergistically inhibited cellular proliferation and induced cellular apoptosis. APG-5918 in combination with alrizomadlin synergistically enhanced antitumor activity in PCa xenograft models in vivo. Mechanistically, PD analysis revealed that APG-5918 downregulated the oncogenic DNA methylation factors (UHRF1, DNMT1) and histone methylation marker H3K27me3. Alrizomadlin markedly downregulated UHRF1 and DNMT1, and upregulated p53 and p21 expression. Combined treatment further enhanced downregulation of DNMT1, UHRF1, cell cycle pathway proteins (pRb, CDK6), antiapoptotic protein MCL-1, and synergistically increased cleavage of PARP-1, a marker of apoptosis. Therefore, the findings provide a scientific rationale for future clinical development of APG-5918 and alrizomadlin to treat patients with PCa. APG-2449, a novel focal adhesion kinase (FAK) inhibitor, inhibits metastasis and enhances the antitumor efficacy of PEGylated liposome doxorubicin (PLD) in epithelial ovarian cancer (EOC) Abstract#: 4569 Time: Tuesday April 9, 2024, 9:00 AM - 12:30 PM (Pacific Time) Introduction: Ovarian cancer is among the leading causes of cancer-related death in women, and most cases are diagnosed at later stages with distant metastasis. FAK overexpression or activation occurs in a substantial proportion of epithelial ovarian cancers (EOCs) and is predictive of poor clinical outcomes. FAK plays an important role in cell migration and chemoresistance, rendering FAK inhibition a promising treatment approach to reduce metastasis of tumor cells and sensitize them to chemotherapy. FAK is therefore emerging as a potential treatment target. The aim of this study was to evaluate the antitumor efficacy of investigational APG-2449, a novel FAK inhibitor, combined with PLD, a commonly used chemotherapy, in relapsed or refractory ovarian cancer. Conclusions: APG-2449 combined with doxorubicin showed synergistic antiproliferative effects in both platinum-resistant and platinum-sensitive ovarian cancer cell lines. FAK inhibition via APG-2449 alone attenuated migration of ovarian cancer cells in a dose-dependent manner. APG-2449 in combination with PLD showed enhanced antitumor activity in platinum-resistant OVCAR-3 ovarian cancer CDX model. The combination regimen prolonged ascites-free and survival times in the ID8-Luc peritoneal syngeneic model. These promising results support the future clinical development of this combination treatment for ovarian cancer. About Ascentage Pharma Ascentage Pharma (6855.HK) is a globally focused biopharmaceutical company engaged in developing novel therapies for cancers, chronic hepatitis B, and age-related diseases. On October 28, 2019, Ascentage Pharma was listed on the Main Board of the Stock Exchange of Hong Kong Limited with the stock code 6855.HK. Ascentage Pharma focuses on developing therapeutics that inhibit protein-protein interactions to restore apoptosis, or programmed cell death. The company has built a pipeline of 9 clinical drug candidates, including novel, highly potent Bcl-2, and dual Bcl-2/Bcl-xL inhibitors, as well as candidates aimed at IAP and MDM2-p53 pathways, and next-generation tyrosine kinase inhibitors (TKIs). Ascentage Pharma is also the only company in the world with active clinical programs targeting all three known classes of key apoptosis regulators. The company is conducting more than 40 Phase I/II clinical trials in the US, Australia, Europe, and China. Ascentage Pharma has been designated for multiple Major National R&D Projects, including five Major New Drug Projects, one New Drug Incubator status, four Innovative Drug Programs, and one Major Project for the Prevention and Treatment of Infectious Diseases. Olverembatinib, the company's core drug candidate developed for the treatment of drug-resistant chronic myeloid leukemia (CML) and the company's first approved product, has been granted Priority Review Designations and Breakthrough Therapy Designations by the Center for Drug Evaluation (CDE) of China National Medical Products Administration (NMPA). To date, the drug had been included into the China 2022 National Reimbursement Drug List (NRDL). Furthermore, olverembatinib has been granted an Orphan Drug Designation (ODD) and a Fast Track Designation (FTD) by the US FDA, and an Orphan Designation by the EMA of the EU. To date, Ascentage Pharma has obtained a total of 16 ODDs from the US FDA and 1 Orphan Designation from the EMA of the EU for 4 of the company's investigational drug candidates. Leveraging its robust R&D capabilities, Ascentage Pharma has built a portfolio of global intellectual property rights and entered into global partnerships with numerous renowned biotechnology and pharmaceutical companies and research institutes such as UNITY Biotechnology, MD Anderson Cancer Center, Mayo Clinic, Dana-Farber Cancer Institute, MSD, and AstraZeneca. The company has built a talented team with global experience in the discovery and development of innovative drugs and is setting up its world-class commercial manufacturing and Sales & Marketing teams. One pivotal aim of Ascentage Pharma is to continuously strengthen its R&D capabilities and accelerate its clinical development programs, in order to fulfil its mission of addressing unmet clinical needs in China and around the world for the benefit of more patients. Forward-Looking Statements The forward-looking statements made in this article relate only to the events or information as of the date on which the statements are made in this article. Except as required by law, Ascentage Pharma undertakes no obligation to update or revise publicly any forward-looking statements, whether as a result of new information, future events, or otherwise, after the date on which the statements are made or to reflect the occurrence of unanticipated events. You should read this article completely and with the understanding that our actual future results or performance may be materially different from what we expect. In this article, statements of, or references to, our intentions or those of any of our Directors or our Company are made as of the date of this article. Any of these intentions may alter in light of future development. SOURCE Ascentage Pharma