FEN1

TORONTO, May 23, 2024 (GLOBE NEWSWIRE) -- Brain Cancer Canada is excited to announce $80,000 research grant has been awarded to Dr. Peter Stirling, PhD, Associate Professor at the University of British Columbia and Senior Scientist at the Terry Fox Laboratory, BC Cancer. This grant supports innovative research aimed at developing bi-functional FEN1 inhibitors that promise to enhance the treatment of glioblastomas by inducing synthetic lethality and stimulating the immune response within tumors. Dr. Stirling's project, titled "Developing new dual function therapies that kill tumour cells and activate immune responses in glioblastomas," targets the aggressive and notoriously treatment-resistant glioblastoma (GBM) tumors. These tumors often suppress local immune responses, making them difficult to treat with conventional chemotherapy alone. The research focuses on a novel chemotherapeutic approach that not only targets tumor cells but also activates the local immune system, potentially overcoming the immune resistance often seen in glioblastomas. The project benefits from the collaboration with experts like Dr. Philip Hieter and Dr. Sheila Singh, who bring specialized knowledge in molecular genetics and clinical practice, respectively. This diverse team will develop therapies that are expected to attack glioblastomas on two fronts: directly killing sensitive tumor cells and recruiting the immune system to tackle resistant cells. Dr. Stirling shared his vision for the project, stating, "Our goal is to transform the treatment landscape for glioblastoma patients by developing therapies that are not only more effective but also harness the body's own immune system to fight cancer. This could significantly improve outcomes for patients facing this challenging diagnosis." Anita Angelini, Vice Chair of Brain Cancer Canada, highlighted the significance of the community and corporate support: "This research is made possible through the generous contributions from Hudson Insurance Group, alongside our dedicated corporate and personal donors. Their support is crucial in bridging the gap between innovative research and tangible treatment advancements." The research integrates cutting-edge technology with clinical insights to address the complex nature of glioblastoma. By focusing on the DNA damage response and its interaction with immune system activation, Dr. Stirling's team is paving the way for novel therapeutic strategies that could substantially impact glioblastoma treatment protocols. This grant follows two other significant research grants issued by Brain Cancer Canada this month, supporting projects led by Dr. Claire Dubois at the Université de Sherbrooke and Dr. Sujoy Banik at London Health Sciences Centre and the Lawson Health Research Institute. Each of these grants is part of Brain Cancer Canada's broader initiative during May's Brain Cancer Awareness Month, known as 'Go Grey in May.' These efforts collectively demonstrate our commitment to advancing research and support for brain cancer patients across Canada. For more details about this ground-breaking research initiative and other efforts by Brain Cancer Canada, please contact sac@braincancercanada.ca Brain Cancer Canada is a national charity dedicated to supporting individuals diagnosed with malignant brain tumors. Through funding innovative research, neurosurgical technology, and advocating for increased options for treatments, Brain Cancer Canada aims to improve survival rates and the quality of life for patients, while providing essential support to their families. Media Contact: Media@braincancercanada.ca

SAN DIEGO, April 10, 2024 /PRNewswire/ -- Blacksmith Medicines, Inc. (Blacksmith), a leading biopharma dedicated to discovering and developing medicines targeting metalloenzymes, today announced preclinical data on its oncology program targeting flap endonuclease 1 (FEN1), a structure-specific metallonuclease that cleaves 5' DNA flaps during replication and repair, at the American Association for Cancer Research (AACR) Annual Meeting 2024, taking place April 5-10 at the San Diego Convention Center, San Diego CA. "FEN1 has been identified as an important therapeutic metalloenzyme involved in DNA replication and repair but previous drug discovery efforts have been hampered by chemistry limitations resulting in inhibitors lacking potency and selectivity," said Zachary Zimmerman, Ph.D. CEO of Blacksmith. "Using our metalloenzyme fragment-based drug discovery approach, we have identified a highly potent and selective inhibitor of FEN1 having synergies with multiple DDR drug classes that include inhibitors of PARP, PARG, USP1, and ATR." The Blacksmith fragment-based drug discovery platform identified a novel metal-binding pharmacophore that binds to the two magnesium ions in the FEN1 active site. Further elaboration using fragment growth strategies resulted in highly potent and selective inhibitors. The current lead (BSM-1516) is ~65-fold more potent against FEN1 than its related enzyme Exonuclease 1 (Exo1) in biochemical assays (IC50 of 7 nM and 460 nM, respectively), an improvement of more than an order of magnitude in selectivity compared to earlier efforts. FEN1 target engagement in live cells was validated by cellular thermal shift assay (CETSA EC50 of 24 nM). Inhibition of FEN1 led to its increased association with chromatin in S-phase cells and recruitment of PARP1 enzyme. In clonogenic assay, BRCA2-deficient DLD1 cells were ~15-fold more sensitive to FEN1 inhibition than their isogenic BRCA2-wild-type counterparts (EC50 of 350 nM and 5 µM, respectively), confirming the increased susceptibility of HR deficient cancer cells to FEN1 inhibition. Treatment of BRCA2-deficient but not wild-type DLD1 cells with BSM-1516 resulted in cell cycle arrest accompanied by DNA damage signaling and accumulation of chromatin-bound RPA32, a marker of ssDNA. In FEN1-inhibitor-anchored CRISPR screen, it was observed that perturbations in EXO1, USP1, PARP1 and HR pathway genes sensitized cells to FEN1 inhibition. Synergistic relationships of BSM-1516 and its combination potential were further explored in viability studies with a panel of DDR inhibitors (n=25) in BRCA2-proficient and deficient cell lines. Strong synergy was identified with multiple drug classes that included inhibitors of USP1 (KSQ-4279), PARP (Olaparib, Niraparib, Talazoparib, AZD5305), PARG (PDD 00017273) and ATR (AZD6738, VE-822, Elimusertib). In vitro ADME assays and in vivo PK studies showed that BSM-1516 has properties suitable for in vivo testing, either as a single agent or in combination with synergistic DDR inhibitors, an investigation that is currently underway. Poster presentation details Abstract Number: 7148 Title: "Small molecule inhibitor of FEN1 nuclease utilizing a novel metal binding pharmacophore synergizes with inhibitors of USP1, PARP, PARG and ATR" Session Category: Experimental and Molecular Therapeutics Session Title: Novel Antitumor Agents 6 Session Date and Time: Wednesday April 10, 2024 9:00 AM - 12:30 PM Location: Poster Section 23 Poster Board Number: 10 About FEN1 Flap endonuclease 1 (FEN1) is a structure-specific di-magnesium metallonuclease that cleaves 5' DNA flaps during replication and repair. FEN1 is an attractive target for development of anticancer therapeutics because it is overexpressed in many tumor types and has a large number of synthetic lethality partners including genes in Homologous Recombination (HR) pathway. About metalloenzymes and the Blacksmith platform Metalloenzymes utilize a metal ion cofactor in the enzyme active site to perform essential biological functions. This diverse class of targets has historically been difficult to drug due to small molecule chemistry limitations that have plagued the industry. The Blacksmith metalloenzyme platform has solved this problem by leveraging the following: A large proprietary fragment library of metal-binding pharmacophores (MBPs); A comprehensive database containing a full characterization of the metalloenzyme genome including functions, metal cofactors, and associations to disease; A first-of-its-kind metallo-CRISPR library of custom single guide RNAs; An industry-leading metalloenzyme computational toolkit for docking, modeling and structure-based drug design; and A robust and blocking intellectual property estate covering bioinorganic, medicinal, and computational chemistry approaches for metalloenzyme-targeted medicines. About Blacksmith Medicines At Blacksmith Medicines, we are developing medicines targeting metal-dependent enzymes. Over 30% of known enzymes are metalloenzymes, covering all major enzyme classes: oxidoreductases, transferases, hydrolases, lyases, isomerases, and ligases. Metal ions, including magnesium, zinc, iron, manganese and copper, are the essential ingredient in these metalloenzymes. We recognized a large unmet need for new chemical matter and innovative approaches to drug this important class of enzymes. Our purpose-built platform for metalloenzyme-targeted medicines combines, for the first time in industry, a focused library of metal-binding pharmacophores with proprietary computational modeling approaches to rapidly and rationally design small molecule inhibitors that interact with key metal ions in the enzyme's active site. Our comprehensive knowledge of the metal environment and key active site interactions enables Blacksmith to rapidly build potent and selective inhibitors in a stepwise and predictable manner. Blacksmith has executed strategic drug discovery collaborations with Basilea Pharmaceutica International Ltd., Cyteir Therapeutics Inc., Eli Lilly and Company (Lilly), Hoffmann-La Roche Ltd., and Zoetis LLC., and has been awarded non-dilutive Federal funding agreements with CARB-X and NIH/NIAID. Blacksmith investors include Lilly, Evotec A.G., MP Healthcare Partners, MagnaSci Ventures, and Alexandria Venture Investments. For further information, please visit the company's website and LinkedIn Media Contact: Amy Conrad Juniper Point [email protected] 858-366-3243 SOURCE Blacksmith Medicines

Researchers describe the biochemical pathway that results in the generation of oxidized mitochondrial DNA, how it is expelled by mitochondria and how it triggers the complex and destructive inflammatory response that follows. Mitochondria are self-contained organelles (they possess their own mini-chromosome and DNA) residing within cells and are charged with the job of generating the chemical energy needed to fuel functions essential to life and well-being. When stressed, damaged or dysfunctional, mitochondria expel their DNA (mtDNA), oxidized and cleaved, into the cytosol -- the fluid within a cell in which organelles float -- and beyond into the bloodstream, triggering inflammation. In autoimmune conditions like lupus and rheumatoid arthritis, the amounts of circulating oxidized mtDNA correlate with disease severity, flare-ups and how well patients respond to therapies. An unanswered question that has plagued the field is whether oxidized mtDNA is simply a biomarker or indicator of disease or something more: a critical player in disease pathology. In a new study, published the July 13, 2022 issue of the journal Immunity, researchers at University of California San Diego School of Medicine, with colleagues elsewhere, describe the biochemical pathway that results in the generation of oxidized mtDNA, how it is expelled by mitochondria and how it triggers the complex and destructive inflammatory response that follows. "In addition to charting a new pathway responsible for the generation of inflammation-provoking fragments of oxidized mtDNA, this work opens the door to the development of new anti-inflammatory agents," said senior study author Michael Karin, PhD, Distinguished Professor of Pharmacology and Pathology at UC San Diego School of Medicine. When macrophages -- a type of white blood cell that detects infections and tissue damage and marshals other immune system cells to respond -- are exposed to metabolic danger signals, one of the immediate responses is for mitochondria to rapidly take up calcium ions from the cytosol, which results in the generation of reactive oxygen species that lead to formation of oxidized mtDNA and the opening of pores in the mitochondrial membranes through which oxidized mtDNA escapes. "However this oxidized mtDNA is large and before it can sneak through the mitochondrial pores, it needs to be chopped into smaller fragments," said Hongxu Xian, PhD, the study's first author and a postdoctoral scholar in Karin's lab. "That job is carried out by an enzyme called FEN1." Once chopped by FEN1, oxidized mtDNA fragments enter the cytosol where they can bind with two different sensors: NLRP3 and cGAS. NLRP3 is part of a multi-protein complex called the inflammasome that activates inflammatory responses. cGAS is an enzyme that generates a small molecule that acts as a chemical messenger to encourage production of other cytokines -- proteins that stimulate, recruit and proliferate immune cells. Together, NLRP3 and cGAS spur inflammation, which in autoimmune diseases has characteristically run amok, prompting the immune system to attack and destroy healthy cells and tissues. The new findings, said Xian, highlight the critical role of FEN1 in fueling the "auto-inflammatory fire." Importantly, Xian and colleagues have demonstrated that FEN1 inhibitors block NLRP3 and cGAS signaling and thereby prevent the onset of the inflammatory process. "This work is important not only because it can explain the origin and pathogenesis of common rheumatic diseases, but it can also lead to the development of new biomarkers and treatments for lupus and arthritis," said Monica Guma, MD, PhD, an associate professor in the UC San Diego School of Medicine and rheumatologist at UC San Diego Health who was not involved in the study.