GPR65

Company Collaborating with Researchers at the University of Nottingham on Optimization and Evaluation of Novel Small Molecule GPR65 Inhibitors in Preclinical Brain Tumor Models OXFORD, England, Sept. 27, 2023 /PRNewswire/ -- Pathios Therapeutics Limited ("Pathios"), a biotech company focused on the development of first-in-class therapies for cancer, today announced that the company has been awarded a £567K (~US$727K) grant from Innovate UK, the UK government's innovation agency. The grant funding will enable the company to expand its development of novel small molecule GPR65 inhibitors into the area of a possible treatment of malignant brain tumors. The project is being conducted in collaboration with researchers from the University of Nottingham and is focused on optimizing small molecule GPR65 inhibitors to penetrate the central nervous system (CNS) and evaluate those optimized compounds in preclinical models of brain cancer. The treatment of patients with malignant brain tumors remains a high unmet medical need. While chemotherapy has modestly improved survival rates among these patients, the need for truly impactful treatments remains. Immunotherapy has demonstrated some promise in this area, though overcoming the immunosuppressive tumor microenvironment (TME) remains a key challenge. Pathios is pursuing a novel immuno-oncology approach to the treatment of cancer focused on counteracting the immunosuppressive polarization of immune cells, including tumor associated macrophages (TAMs), that is triggered by an acidic TME. This is achieved by the design and development of inhibitors of GPR65, an acid sensing G protein-coupled receptor that is exclusively expressed on immune cells and is associated with driving the immunosuppressive immune cell phenotype in the TME that prevents immune-mediated killing of cancer cells. Pathios' internal human genetic analysis demonstrates that reductions in GPR65 function are associated with significantly improved survival across a range of solid tumor types, positioning it as a unique immuno-oncology target for therapeutic intervention. With this grant, Pathios is utilizing an extensively developed proprietary assay platform to optimize CNS penetration of small molecule GPR65 inhibitors for the treatment of human malignant gliomas. Optimized GPR65 inhibitors are being tested in a human ex vivo co-culture system model of human glioblastoma in collaboration with University of Nottingham researchers, followed by in vivo efficacy evaluation in mouse models. "Recent research suggests that a portion of glioblastoma patients do not respond to approved immuno-oncology drugs due to the immunosuppression of immune cells in the TME by the acidic microenvironment inherent to all solid tumors, including brain cancers." said Stuart Hughes, Ph.D., chief executive officer of Pathios. "We believe there is promise in applying our novel immuno-oncology approach to cancers of the brain with a CNS-penetrating small molecule GPR65 inhibitor. We are excited to be working alongside the talented team at the University of Nottingham on this important preclinical research, which we hope will pave the way for future clinical studies." "We are excited to be supporting the research and development of this novel therapy for malignant brain tumours. By working with Pathios we aim to support their preclinical development and expedite the progress of their inhibitors into the clinic," said Alan McIntyre, Associate Professor of Faculty of Medicine & Health Sciences, at the University of Nottingham . "This is important as malignant brain tumours are difficult to treat. In addition, this approach offers a new avenue to overcome the therapy resistance caused by the acidic microenvironment, frequently found in malignant brain tumours." About Acidity in the Tumor Microenvironment The acidic tumor microenvironment, inherent to many cancers, causes a profound immunosuppression of infiltrating immune cells. This environment disarms the anti-cancer immune response and negates the effectiveness of current immunotherapies. This is particularly evident in tumor associated macrophages (TAM), where acidity is sensed by the cell-surface receptor GPR65, leading to an induction of the transcriptional repressor ICER (inducible cAMP early repressor) and the widespread suppression of a host of pro-inflammatory mediators and anti-tumorigenic genes. About Pathios Therapeutics Launched in 2017, Pathios is a drug discovery and development company focused on translating innovative science into new medicines. Pathios was founded by a team of experienced biotech and pharmaceutical industry professionals, entrepreneurs, and clinicians. The company is focused on developing small molecule inhibitors of the pH-sensing G protein-coupled receptor GPR65 to counteract the GPR65 mediated immunosuppressive polarization of immune cells, including tumor associated macrophages, that is triggered by an acidic tumour microenvironment present in most cancers. To date, Pathios has raised a total of US$33M in Series A funding from the leading venture capital firms, Canaan Partners and Brandon Capital. Pathios is headquartered at the Innovation Centre on Milton Park, a key science precinct south of Oxford, UK. For more information, please visit . About the University of Nottingham Ranked in the Top 100 globally and 17th in the UK by the QS World University Rankings2024, the University of Nottingham is a founding member of Russell Group of research-intensive universities. Studying at the University of Nottingham is a life-changing experience, and we pride ourselves on unlocking the potential of our students. We have a pioneering spirit, expressed in the vision of our founder Sir Jesse Boot, which has seen us lead the way in establishing campuses in China and Malaysia - part of a globally connected network of education, research and industrial engagement. The University is among the best universities in the UK for the strength of our research, positioned seventh for research power in the UK according to REF 2021. The birthplace of discoveries such as MRI and ibuprofen, our innovations transform lives and tackle global problems such as sustainable food supplies, ending modern slavery, developing greener transport, and reducing reliance on fossil fuels. The University is a major employer and industry partner - locally and globally - and our graduates are the second most targeted by the UK's top employers, according to The Graduate Market in 2022 report by High Fliers Research. We lead the Universities for Nottingham initiative, in partnership with Nottingham Trent University, a pioneering collaboration between the city's two world-class institutions to improve levels of prosperity, opportunity, sustainability, health and wellbeing for residents in the city and region we are proud to call home. More news… About Innovate UK Innovate UK drives productivity and economic growth by supporting businesses to develop and realise the potential of new ideas. We connect businesses to the partners, customers and investors that can help them turn ideas into commercially successful products and services and business growth. We fund business and research collaborations to accelerate innovation and drive business investment into R&D. Our support is available to businesses across all economic sectors, value chains and UK regions. Innovate UK is part of UK Research and Innovation. For more information visit Contacts: Pathios Therapeutics Stuart Hughes, Chief Executive Officer +44 1235 644 960 [email protected] Vida Strategic Partners (on behalf of Pathios Therapeutics) Tim Brons +1 646 319 8981 [email protected] SOURCE Pathios Therapeutics

Latest Small Molecule to Emerge from GPR65 Discovery Program Counteracts Immunosuppressive Polarization of Macrophages Triggered by an Acidic Tumor Microenvironment (TME) Drives Infiltration of T Cells and NK Cells into TME Leading to Impressive Anti-Tumor Activity in Preclinical Cancer Models Following Oral Dosing Pathios Therapeutics Limited ("Pathios"), a biotech company focused on the development of first-in-class therapies for cancer, today announced the presentation of the latest preclinical data from the company's GPR65 discovery program at the American Association for Cancer Research (AACR) Annual Meeting 2023. The presentation included the public unveiling of PTT-4256, an internally discovered, oral, highly potent, and selective small molecule inhibitor of GPR65 that has demonstrated excellent drug-like properties and impressive monotherapy anti-tumor activity in preclinical models. The data were featured in a poster presentation at the AACR annual meeting, being held April 14-19, 2023, in Orlando, Florida. Pathios is pursuing a novel immuno-oncology approach to the treatment of cancer focused on counteracting the immunosuppressive polarization of tumor associated macrophages (TAMs) that is triggered by a highly acidic tumor microenvironment (TME). It does so by targeting GPR65, an acid sensing G protein-coupled receptor that is exclusively expressed on immune cells and is associated with driving the immunosuppressive TAM phenotype that prevents immune-mediated killing of cancer cells. Pathios' internal human genetic analysis demonstrates that reductions in GPR65 function are associated with significantly improved survival across a range of solid tumor types, positioning it as a unique immuno-oncology target for therapeutic intervention. Data presented at AACR highlighted the company's discovery and advancement of PTT-4256, which exhibits high potency for GPR65 (IC50 Stuart Hughes, Ph.D., chief executive officer of Pathios. "Based on these latest data, we are now focused on completing the toxicology program that will support initiation of clinical trials in 2024. As we look ahead to our entry into the clinic, we continue to be utterly compelled by the promise of this novel immuno-oncology target, in particular noting the human genetic validation which we believe sets GPR65 inhibition apart from other approaches in the field." About Acidity in the Tumor Microenvironment The acidic tumor microenvironment, inherent to many cancers, causes a profound immunosuppression of infiltrating immune cells. This environment disarms the anti-cancer immune response and negates the effectiveness of current immunotherapies. This is particularly evident in tumor associated macrophages (TAM), where acidity is sensed by the cell-surface receptor GPR65, leading to an induction of the transcriptional repressor ICER (inducible cAMP early repressor) and the widespread suppression of a host of pro-inflammatory mediators and anti-tumorigenic genes. About Pathios Therapeutics Launched in 2017, Pathios is a drug discovery and development company focused on translating innovative science into new medicines. Pathios was founded by a team of experienced biotech and pharmaceutical industry professionals, entrepreneurs, and clinicians. The company is focused on developing small-molecule inhibitors of the pH-sensing G protein-coupled receptor GPR65 to target immunosuppressive macrophages in advanced cancers. To date, Pathios has secured a total of US$33M in Series A funding from the leading venture capital firms, Canaan Partners and Brandon Capital. Pathios is headquartered at the Innovation Centre on Milton Park, a key science precinct south of Oxford, UK. SOURCE Pathios Therapeutics The content above comes from the network. if any infringement, please contact us to modify.

There’s a receptor on cells in the gut thought to be associated with a range of gastrointestinal disorders. Some efforts are underway to target this receptor to treat gut inflammation. ThirtyFiveBio is pursuing the target to treat cancer and the biotech startup has chosen the American Association for Cancer Research’s (AACR) annual meeting to reveal its science. The name of Oxford, U.K.-based ThirtyFiveBio comes from the receptor it’s targeting: GPR35. This receptor belongs to the family of proteins known as G-protein coupled receptors, or GPCRs. The involvement of this protein family in biological processes throughout the body make it valuable for drug research. But less is known about some GPCRs, leaving their role as drug targets less certain. GPR35 is one of these so-called orphans. Orphan GPCRs don’t have endogenous ligands, the substances in the body that can bind to it to produce some sort of an effect. Without known endogenous ligands, it’s hard for drug hunters to completely understand these receptors—that’s why they’re called orphans. GPR35 was discovered in 1998. Subsequent research linked it to a wide range of disorders, including inflammatory bowel disease, type 2 diabetes, and coronary artery disease. In more recent years, research has yielded genetic insights showing that variants in the GPR35 gene are associated with disease in the gut, said ThirtyFiveBio CEO James Westcott. Those insights have sparked new research at several companies. Tokyo-based Sosei Heptares has technology that stabilizes GPCRs, aiding in the development of molecules that can target them—including orphan receptors. GPR35 is the focus of Sosei Heptares’s GSK alliance, which started in 2020. The deal gives the pharmaceutical giant rights to Sosei Heptares’s agonists, molecules designed to activate the receptor. In addition to a lead compound in preclinical development for inflammatory bowel disease and other gastrointestinal immune disorders, the deal includes back-up compounds that target GPR35. Intrinsic Medicine is developing drugs derived from carbohydrates found in human milk. The Seattle company’s preclinical pipeline includes one compound, OM003, an agonist of GPR35 that is being researched as a potential way of treating immune-mediated disorders and inflammatory disorders of the gastrointestinal tract. ThirtyFiveBio is taking the opposite approach by developing drugs that block GPR35. Westcott said his company’s research into human data shows that the receptor is switched on in diseases states, suggesting that turning it off would be a better way to affect disease. At AACR on Sunday, ThirtyFiveBio is presenting its GPR35 research. In an abstract submitted for the conference, the company notes that a fatty diet combined with metabolism in the gut can lead to high levels of secondary bile acids that raise the cancer risk. These bile acids can activate GPR35. ThirtyFiveBio’s drug discovery work has yielded small molecules that block GPR35 signaling that promotes cancer. These molecules also block the signaling that comes from secondary bile acids. Westcott said ThirtyFiveBio has four compounds that have reached lead optimization. The company won’t be disclosing their chemical structures at AACR. The presentation will focus on the startup’s research into GPR35, he said. The company will also show it has potent inhibitors of the receptor whose mechanism of action is understood. “We’ve validated the hypothesis in translational models of disease,” Westcott said. “That’s what we’ve done to step out and tell the world about.” ThirtyFiveBio’s science is rooted in M:M Bio, a company that has a record of incubating and starting biotechnology firms. Pathios Therapeutics was the first one, founded in 2017. That startup’s research focuses on another orphan, GPR65, for potential applications in cancer immunotherapy. Bioinformatic analysis of that receptor also turned up signals indicating that blocking GPR35 could be promising as well, Westcott said. Pathios’s 2019 Series A financing included an investment from venture capital firm Canaan Partners, whose portfolio includes cancer drug developers Rondo Therapeutics and Day One Biopharmaceuticals. In 2021, M:M Bio founded ThirtyFiveBio in partnership with Canaan. To date, the startup has raised $20 million in seed financing. With the preclinical data the it has generated, Westcott said the company will look to extend that financing to validate the path to human testing. He added that ThirtyFiveBio would look to raise a Series A financing in “a couple of years” to reach the clinic.