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OXFORD, United Kingdom, Oct. 10, 2024 (GLOBE NEWSWIRE) -- MitoRx Therapeutics (MitoRx), a platform biotechnology company developing novel mitochondrial-targeted sulfide-donor therapeutics (mtH2SD) in obesity-related disorders and myopathies announces a publication in Elsevier’s prestigious biomedical sciences journal Pharmacological Research. The work led by collaborators at Jagiellonian University Medical College showed that in a preclinical mouse study involving high-fat diet (HFD)-induced obesity, the company’s mtH2SD compound AP39, significantly slowed the rate of gain in weight. This is the first comprehensive study designed to test whether mitochondrial sulfide donors could address weight gain and fatty liver (steatosis). Mounting evidence suggests that hydrogen sulfide is an important signalling molecule in the liver, regulating lipid metabolism and mitochondrial function, but its direct delivery to mitochondria had not been investigated as a therapeutic strategy in obesity-related metabolic disorders. This is what the Pharmacological Research paper examined. MitoRx’s CSO, Prof Matt Whiteman, and their Senior Discovery Chemist, Dr. Roberta Torregrossa, with co-inventor Dr. Mark Wood at the University of Exeter are co-authors on the paper. It showed that treatment with AP39 reduced weight gain in animals fed HFD by 32% at the end of the research. (1) AP39 is a versatile mtH2SD tool compound that mediates very large and statistically significant reductions in liver steatosis, large and significant reductions in triglycerides, reductions in de novo lipogenesis, reductions in inflammatory markers, and significant downregulation of known liver proteomic markers of weight gain and the development of obesity, indicating mtH2SD-mediated downregulation mTOR/SREBP-1/SCD1 pathway alleviates obesity. MitoRx is developing undisclosed next-generation mtH2SDs to take to the clinic. Importantly, this modality is both muscle protective including in a severe fibrotic muscle atrophy model and is also anti-obesogenic. With this double therapeutic benefit, MitoRx’s next-gen mtH2SDs could potentially address the loss of lean muscle mass which is a serious side effect of marketed GLP-1 receptor agonist drugs in general, especially with age. This approach could be applicable in sarcopenic (age-related muscle mass and strength loss) obesity while also addressing muscle wasting in obese patients in general. Dr. Jon Rees, Chief Executive Officer of MitoRx, said: “MitoRx is advancing its first-in-class mitochondriotropic platform initially focused on myopathies and is now applying it to obesity offering a small molecule anti-obesogenic which is also muscle protective. This latest publication provides solid pre-clinical evidence that AP39 substantially suppressed the gain of weight in HFD-fed animals, suggesting a new pathway to alleviate obesity, whilst avoiding the muscle wasting side-effects that blight GLP-1 receptor agonist drugs. Powerful international research collaborations like this, with the talented team at Jagiellonian University’s Faculty of Medicine, help speed therapeutic advances to patients.” Dr. Aneta Stachowicz, Department of Pharmacology at the Faculty of Medicine, Jagiellonian University Medical College, Poland, and lead author of the Pharmacological Research paper, said: “Having comprehensively demonstrated that mitochondrial-targeted sulfide donors alleviate weight gain and significantly reduce multiple markers of obesity, we mark the beginning of a new era in the development of an innovative therapeutic approach for metabolic disease through the modulation of mitochondrial sulfide-signalling.” Matt Whiteman, Professor of Experimental Therapeutics at the University of Exeter Medical School, UK, and co-author of the study added: We discovered impaired sulfide metabolism in overweight patients with type 2 diabetes in 2010 (2) and we noticed that this impairment was driven by the amount of fat tissue these individuals were carrying; an observation since confirmed by many others. These findings suggested that treating this impairment with mtH2SD could potentially treat diabetes, obesity and complications arising from having too much fat in the body. It is gratifying to now translate those observations toward clinically viable drugs with MitoRx References: (1): Mitochondria-targeted hydrogen sulfide donor reduces fatty liver and obesity in mice fed a high fat diet by inhibiting de novo lipogenesis and inflammation via mTOR/SREBP-1 and NF-Kappa-B signaling pathways. Pharmacological Research 209 (2024):107428https://doi.org/10.1016/j.phrs.2024.107428 (2): Adiposity is a major determinant of plasma levels of the novel vasodilator hydrogen sulphide. Diabetologia 53(8):1722-6 (2010). https://doi.org/10.1007/s00125-010-1761-5 Company Contact (MitoRx) Jon Rees, CEOEmail: jon.rees@mitorxtherapeutics.com Phone: +44(0)7826 556622 Media Contact (Scius Communications for MitoRx) Katja Stout, Managing PartnerEmail: katja@sciuscommunications.com Phone: +44(0)7789 435990 University of Exeter Press Office  +44 (0)1392 722405 or 722062pressoffice@exeter.ac.uk Jagiellonian University Marcin Kubatrzecznik@uj.edu.pl About MitoRx TherapeuticsAt MitoRx our mission is to become the leading global developer of medicines arresting the progression of degenerative diseases driven by mitochondrial dysfunction. We are a preclinical stage biotechnology company developing our first-in-class first-in-target, mitochondriotropic therapeutics in obesity-related indications and myopathies. Located in Harwell, Oxford, we have raised £5.4m seed financing from investors including the UK Innovation & Science Seed Fund, the Fink Family Office, Oxford Technology Management, Empirical Ventures, Wren Capital and Longevitytech.fund, as well as angel investors. For more information visit our website at www.mitorxtherapeutics.com and follow us on LinkedIn. About the University of ExeterThe University of Exeter is a Russell Group university that combines world-class research with high levels of student satisfaction. Exeter has over 30,000 students and sits within the Top 15 universities in The Complete University Guide 2025, and tenth in the world in the Times Higher Education (THE) Impact Rankings. In the 2021 Research Excellence Framework (REF), more than 99% of our research were rated as being of international quality, and our world-leading research impact has grown by 72% since 2014, more than any other Russell Group university.https://www.exeter.ac.uk/ About Jagiellonian University The Jagiellonian University is the oldest higher education institution in Poland and one of the oldest in Europe. It was founded on 12 May 1364 by the Polish king Casimir the Great. The Jubilee year 2014 marked the 650th anniversary of this remarkable event. Since its very beginning, the Jagiellonian University has been an international institution. Today, the Jagiellonian University comprises 16 Faculties, where nearly 4 thousand academic staff conduct research and provide education to over 40 thousand students, within the framework of more than 80 different fields of study. The eminent researchers and state-of-the-art infrastructure make the JU one of the leading Polish scientific institutions, collaborating with major academic centres from all over the world. The Jagiellonian University is also home to about 150 student societies, where young researchers pursue their academic interests and develop friendships with people who share their passion. For more information visit our website at https://en.uj.edu.pl/en.

Sterol regulatory element-binding proteins (SREBPs) play a crucial role in lipid biosynthesis. In a recent study, researchers identified a novel cleavage enzyme of SREBP-1c, a key player in fatty acid biosynthesis. Moreover, the team unveiled, for the first time, that the biosynthesis process of fatty acid in the liver is activated by saturated fatty acids and inhibited by polyunsaturated fatty acids, providing new insights into the intricate workings of this cleavage system. Researchers have been studying the transcription factor SREBP, a critical regulator of lipid biosynthesis. Precursor SREBP proteins, located in the endoplasmic reticulum (ER) of the cell, are transported through the golgi apparatus to the nucleus. Here, they promote the transcription of genes associated with lipid biosynthesis, playing a pivotal role in regulating cholesterol. SREBP-1c, a specific member of the SREBP family, is known to activate fatty acid synthesis. Interestingly, this process is inhibited by polyunsaturated fatty acids. The exact mechanism behind this regulation, however, remains to be elucidated. The research team elucidated a novel cleavage mechanism of SREBP-1c, a protein involved in fatty acid synthesis, and confirmed its regulation by fatty acids. The cleavage of SREBP-1c occurs in the endoplasmic reticulum, with the rhomboid protease RHBDL4, located in the ER membrane, identified as a new cleavage enzyme for SREBP-1c. This cleavage process is activated by saturated fatty acids and deactivated by polyunsaturated fatty acids, suggesting that RHBDL4's activity is modulated by the type of fatty acid. Additionally, the team discovered a unique mechanism where the VCP complex extracts the cleaved SREBP-1c protein from the endoplasmic reticulum. In the livers of mice deficient in the RHBDL4 gene and fed a high-fat and high-cholesterol diet, the activation of SREBP-1c cleavage was suppressed. This inhibited the expression of a group of target genes involved in fatty acid synthesis, polyunsaturated fatty acid synthesis and uptake, and lipoprotein secretion, which improved fatty liver pathophysiology, as observed in wild-type mice. The RHBDL4-SREBP-1c pathway, uncovered in this study, represents a lipid homeostasis mechanism regulated by fatty acids. This groundbreaking discovery is anticipated to pave the way for developing new therapeutic strategies for metabolic disorders and lifestyle-related diseases stemming from abnormal lipid metabolism. This work was supported by Grants-in-Aid for Scientific Research on Innovative Areas program (Inflammation Cellular Sociology) JP17H06395 (to H.S.), Scientific Research (A) 15H02541 and 18H04051 (to H.S.), and Scientific Research (C) 16K01811 and 19K11737 (to S.-I.H.) from the Ministry of Science, Education, Culture, and Technology of Japan; AMED-CREST Grant Number 16gm0910003h0002 (to H.S.) from the Japan Agency for Medical Research and Development, AMED; and Ono Medical Research Foundation (to S.-I.H.).

Protein arginine methyltransferases (PRMTs) are catalytic enzymes for arginine methylation, capable of methylating a variety of proteins and playing pivotal roles in biological processes such as gene expression, splicing, and DNA damage repair.  Currently, 9 members of the PRMTs family has been identified, divided into three major types. Type I, catalyzes the formation of asymmetric dimethylarginine and includes PRMT1, PRMT2, PRMT3, PRMT4, PRMT6, PRMT8. Type II catalyzes the formation of symmetric dimethylarginine and includes PRMT5 and PRMT9. Type III is responsible for the formation of monomethylarginine and includes only PRMT7.  PRMT5 is the most highly studied subtype of PRMT, forming a heterooctameric complex with Methylosome protein 50 (MEP50), enabling the symmetrical dimethylation of a variety of substrates, including histone and non-histone proteins. PRMT5 histone substrates primarily include H4 residue Arg3 (H4R3), H3 residue Arg2 (H3R2), Arg8 (H3R8), and H2A residue Arg3 (H2AR3), whose symmetric dimethylation is related to gene transcription regulation. Non-histone substrates of PRMT5 include Sm proteins, nucleolar proteins, RAF proteins, EGFR, androgen receptor (AR), tumor suppressor p53, IL-2, HOXA9, NFkB, KLF4, GATA4, PDCD4, E2F-1, SPT5, GM130, POLR2A, SREBP1a, Rad9, and more that are involved in regulating cellular signalling, differentiation, DNA repair, and mRNA splicing among other cellular processes.  Research has found that PRMT5 is overexpressed in various types of cancer, such as glioblastoma, melanoma, leukemia/lymphoma, multiple myeloma, prostate cancer, bladder urothelial carcinoma, ovarian cancer, lung cancer, gastric cancer, and colorectal cancer. Furthermore, PRMT5 expression is associated with a poor prognosis in tumor progression and metastasis. Further research has shown that PRMT5 directly affects the growth and differentiation of tumor cells by regulating multiple genes such as p53, IL-2, TRAIL receptor, MITF, transcription factor E2F-1, and tumor suppressor gene 7. Additionally, PRMT5 has been found to constitute "synthetic lethal" partnerships with gene mutations like methylthioadenosine phosphorylase (MTAP), metabolic enzyme methionine adenosyltransferase 2 alpha (MAT2A), and others.  Both in vitro and in vivo studies have shown that inhibition or knockdown of PRMT5 significantly reduces cell proliferation, migration, and colony formation, but promotes apoptosis and cell cycle arrest. Furthermore, oral PRMT5 inhibitors demonstrate significant antitumor activity in lung tumor xenograft models. Thus, PRMT5 has become a new target for the development of epigenetic anti-cancer drugs. PRMT5 Competitive LandscapeAccording to the data provided by Patsnap Synapse-Global Drug Intelligence Database: the following figure shows that as of 22 Sep 2023, there are a total of 41 PRMT5 drugs worldwide, from 39 organizations, covering 28 indications, and conducting 20 clinical trials. 👇Please click on the picture link below for free registration or login directly if you have freemium accounts, you can browse the latest research progress on drugs , indications, organizations, clinical trials, clinical results, and drug patents related to this target. Based on the analysis of target PRMT5, it can be concluded that several companies, including GSK Plc, Ipsen SA, Tango Therapeutics, Inc., Amgen, Inc., Mirati Therapeutics, Inc., and Prelude Therapeutics, Inc., are actively involved in the research and development of drugs targeting PRMT5. These companies have drugs in various stages of development, with some reaching advanced stages such as Phase 2. The indications for these drugs cover a wide range of cancer types, indicating the potential of PRMT5 as a therapeutic target. Small molecule drugs and chemical drugs are the most rapidly progressing drug types under the target PRMT5, with small molecule drugs being the primary focus. The United States, China, and Canada are the countries/locations with the highest development activity, with the United States leading in Preclinical stage and China showing progress in Phase 1. Overall, the current competitive landscape suggests a promising future for the development of PRMT5 inhibitors in the pharmaceutical industry. PRMT5 inhibitors entering Phase II clinical studies: GSK-3326595GSK-3326595 is a small molecule drug that is being developed by Epizyme, Inc. It is designed to target PRMT5, a protein involved in various cellular processes. The drug is being investigated for its potential therapeutic applications in neoplasms, immune system diseases, and hemic and lymphatic diseases. The active indications for GSK-3326595 include solid tumors, non-Hodgkin lymphoma, neoplasms, acute myeloid leukemia, and myelodysplastic syndromes. These are all serious and potentially life-threatening conditions that affect different parts of the body, including the blood, lymph nodes, and various organs. 👇Please click on the image below to directly access the latest data (R&D Status | Core Patent | Clinical Trial | Approval status in Global countries) of this drug. Currently, GSK-3326595 is in Phase 2 of clinical development, which means that it has already undergone initial testing in humans and has shown promising results in terms of safety and efficacy. Phase 2 trials typically involve a larger number of participants and aim to further evaluate the drug's effectiveness and side effects. As a small molecule drug, GSK-3326595 has the advantage of being able to penetrate cells and interact with specific targets, such as PRMT5. This targeted approach can potentially lead to more effective treatment options with fewer side effects compared to traditional chemotherapy or radiation therapy. Epizyme, Inc. is the originator organization behind GSK-3326595. They are a biopharmaceutical company focused on developing novel therapies for patients with genetically defined cancers and other diseases. With their expertise in epigenetics and targeted therapies, Epizyme is dedicated to advancing the field of biomedicine and improving patient outcomes. In summary, GSK-3326595 is a small molecule drug being developed by Epizyme, Inc. It targets PRMT5 and has potential applications in neoplasms, immune system diseases, and hemic and lymphatic diseases. The drug is currently in Phase 2 of clinical development and shows promise in treating solid tumors, non-Hodgkin lymphoma, acute myeloid leukemia, and myelodysplastic syndromes. Epizyme, Inc. is the organization behind the development of this innovative drug, aiming to provide new treatment options for patients in need. PRMT5 inhibitors entering PhaseⅠ/Ⅱclinical studies: AMG-193AMG-193 is a small molecule drug developed by Amgen, Inc. It falls under the therapeutic areas of neoplasms and respiratory diseases, specifically targeting PRMT5. The drug is primarily indicated for the treatment of non-small cell lung cancer and solid tumors. 👇Please click on the image below to directly access the latest data (R&D Status | Core Patent | Clinical Trial | Approval status in Global countries) of this drug. Amgen, Inc. is the originator organization behind AMG-193. Being a small molecule drug, AMG-193 is designed to interact with PRMT5, a target protein involved in various cellular processes. By specifically targeting PRMT5, the drug aims to inhibit its activity and potentially disrupt the growth and survival of cancer cells in non-small cell lung cancer and solid tumors. Neoplasms, or abnormal tissue growth, encompass a wide range of cancers. Non-small cell lung cancer is one of the most common types of lung cancer, accounting for approximately 85% of all cases. Solid tumors, on the other hand, refer to abnormal masses of tissue that can occur in various organs, such as the breast, colon, or prostate. The current development stage of AMG-193, Phase 1/2, suggests that the drug has undergone initial testing in a small group of patients to evaluate its safety, dosage, and potential efficacy. This phase typically involves assessing the drug's pharmacokinetics, side effects, and preliminary therapeutic effects. The fact that AMG-193 has obtained IND approval in China indicates that it has met the necessary regulatory requirements to proceed with clinical trials in the country. In summary, AMG-193 is a small molecule drug developed by Amgen, Inc. that targets PRMT5. It is indicated for the treatment of non-small cell lung cancer and solid tumors. The drug has reached Phase 1/2 on a global scale and has obtained IND approval in China, allowing for further clinical trials in the country.