METTL1

Data demonstrates pharmacological inhibition of METTL1 inhibits tumour growth and reduces tRNA methylation and stability of tRNAs CAMBRIDGE, England, Feb. 22, 2024 /PRNewswire/ -- STORM Therapeutics Ltd. (STORM), the clinical stage biotechnology company discovering and developing novel small molecule therapies targeting RNA modifying enzymes (RMEs) for oncology and other diseases, today announced that Alexandra Sapetschnig, Group Leader at STORM, will present results and conclusions on its METTL1 tRNA methyltransferase program at the ESMO Targeted Anticancer Therapies Congress 2024 in Paris, France on 26 February. The presentation entitled "Targeting the tRNA methyltransferase METTL1 with small molecule inhibitors in cancer" illustrates STORM's new data showing that pharmacological inhibition of a tRNA methyltransferase affects tumour growth in animal models. Data demonstrated that: Two distinct chemical series exhibit METTL1 inhibition in vitro at low nanomolar concentrations while displaying high selectivity over other RNA and protein methyltransferases. Mechanistically, METTL1 inhibition leads to reduced tRNA methylation and stability of a subgroup of tRNAs. In several cancer cell lines, METTL1 inhibition impairs cell proliferation and cell cycle progression accompanied by reduced expression of cell cycle regulators. In vivo, METTL1 inhibitors induce tumour growth inhibition in both immune-deficient and immune-competent mouse strains. Oliver Rausch, Chief Scientific Officer at STORM Therapeutics, said: "We are delighted to present this exciting new work which demonstrates that targeting specific tRNA pathways via inhibition of the novel RNA methyltransferase METTL1 results in cancer cell reprogramming and profound cancer growth inhibition in vivo. This follows hot on the heels of our groundbreaking work on METTL3 leading to the discovery of STC-15, currently in clinical testing for advanced malignancies, and highlights the immense potential of targeting RNA modifications for the development of new cancer treatments. As we continue to advance and develop our novel proprietary drug discovery pipeline, these new findings illustrate the advancements that STORM are making to transform the treatment landscape for cancer. All accepted abstracts will be published online only in the ESMO TAT 2024 Abstract Book, a supplement to the ESMO journal, ESMO open. Details of the conference and poster presentation are as follow: Poster Title: Targeting the tRNA methyltransferase METTL1 with small molecule inhibitors in cancer Presenter: Alexandra Sapetschnig1, Beth Thomas1, Eliza Yankova2, Harry Fischl1, Aleksandra Azevedo1, Sarah Bucknell1, Richard Fosbeary1, Sapphire Sawyer1, Sian Evans2, Carmen Livi1, Byron Andrews1, Jack Rogan1, Natalie Webster1, Matthew Fyfe1, Konstantinos Tzelepis2, Oliver Rausch1 Date and Time: 26 February 2024 at 17:15 – 18:15 CET Session: Cocktail and Poster Display Session Location: Hall Bordeaux Presentation Number: 105P 1 Storm Therapeutics Ltd, Babraham Research Campus, Cambridge CB22 3AT, United Kingdom 2 Wellcome-MRC Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, University of Cambridge, Puddicombe Way, Cambridge CB2 0AW, United Kingdom NOTES TO EDITORS About STORM Therapeutics STORM Therapeutics (STORM) is a clinical stage biotechnology company creating novel therapies that inhibit RNA modifying enzymes (RME) for use in oncology and other diseases. There are more than 150 RNA modifications reported and approximately 300 RNA modifying enzymes which represent novel therapeutic targets. STORM has leveraged its first-mover advantage to establish a novel drug discovery and RNA analytics platform leading to the identification of novel targets and a proprietary pipeline of first-in-class small-molecule drug candidates for potential use in oncology, inflammation, viral infection and CNS diseases. The pipeline is exemplified by STORM's METTL3 inhibitor, STC-15, which has received IND approval and commenced its Phase 1 clinical study in cancer patients in November 2022. STC-15 represents the first ever RNA modifying enzyme inhibitor to enter clinical evaluation in humans. Additional programs are planned for advancement into IND-track activities in 2024. STORM investors include M Ventures, Pfizer Ventures, Taiho Ventures LLC, Seroba Life Sciences, Cambridge Innovation Capital I Limited, IP Group plc, UTokyo Innovation Platform Co., Ltd. (UTokyo IPC) and the Fast Track Initiative (FTI). For more information, please visit About STC-15 STORM's lead clinical program STC-15 is a first-in-class inhibitor of RNA modification and is the first ever RNA methyltransferase inhibitor to enter clinical development. STC-15 is an oral small molecule that inhibits METTL3, an RNA methyltransferase implicated in oncology and other diseases. Certain RNA methyltransferases are important regulators of RNA sensing and innate immune activation and represent novel immune-regulatory targets. STC-15 has also been shown preclinically to inhibit tumour growth through mechanisms involving anti-cancer immune responses, such as changes in interferon signalling and synergy with T cell checkpoint blockade. STORM commenced the dosing of the first patient in a Phase 1 clinical study of STC-15 in patients living with solid tumours in November 2022 and anticipates presenting first results from its study in 2024. Details of the study can be found on clinicaltrials.gov under the identifier NCT05584111. About ESMO ESMO's core mission is to improve the quality of cancer care, from prevention and diagnosis all the way to palliative care and patient follow-up. It is to educate – doctors, cancer patients and the general public – on the best practices and latest advances in oncology. And it is to promote equal access to optimal cancer care for all patients. SOURCE STORM Therapeutics

Data demonstrates METTL1 inhibition in vitro at low nanomolar concentrations while displaying high selectivity over other RNA and protein methyltransferases Data provides the first proof-of-concept that pharmacological inhibition of a tRNA methyltransferase affects tumour growth in vitro and in animal models CAMBRIDGE, England, Dec. 8, 2023 /PRNewswire/ -- STORM Therapeutics Ltd. (STORM), the clinical stage biotechnology company discovering and developing novel small molecule therapies targeting RNA modifying enzymes (RMEs) for oncology and other diseases, is pleased to announce that data on its METTL1 tRNA methyltransferase inhibitor will be presented by collaborator Dr Konstantinos Tzelepis at the 65th Annual ASH Meeting in San Diego, USA on Friday 8 December, 2023. The presentation entitled "Overcoming Therapy Resistance in AML Using Novel Epitranscriptomic Modalities" details results showing that pharmacological inhibition of a tRNA methyltransferase affects tumour cell growth in in vitro and in vivo models. Preclinical data demonstrated that: STORM METTL1 inhibitors exhibit METTL1 inhibition in vitro at low nanomolar concentrations while displaying high selectivity over other RNA and protein methyltransferases. Mechanistically, METTL1 inhibition leads to reduced tRNA methylation and reduced stability of a subgroup of tRNAs. In several cancer models, METTL1 inhibition impairs cell proliferation and cell cycle progression accompanied by elevation of differentiation markers. In vivo, METTL1i treatment induced strong tumour growth inhibition in cell-line derived xenografts and syngeneic in vivo cancer models (haematological and solid malignancies). Jerry McMahon, Chief Executive Officer & President of STORM Therapeutics, said: "It is very exciting to be able share for the first time that inhibition of the tRNA methyltransferase METTL1 with a small molecule shows anti-cancer properties. We continue to expand our pipeline of novel and proprietary chemistries to modulate enzymes which modify RNA. We look forward to advancing our first-in-class METTL1 program towards the clinic." Dr Konstantinos Tzelepis, Principal Investigator at University of Cambridge and Cambridge Stem Cell Institute, commented: "We are very excited to present novel data on the development and characterisation of the first-in-class bioavailable tRNA methyltransferase inhibitor against METTL1. This is a fantastic collaborative effort which expands significantly the therapeutic landscape of the epitranscriptomics field and capitalises on our previous published work which shown that METTL1 is a key player in oncogenesis." Details of the conference and presentation are as follow: Presented Talk Title: Overcoming Therapy Resistance in AML Using Novel Epitranscriptomic Modalities Presenter: Dr Konstantinos Tzelepis, Principal Investigator, University of Cambridge and Wellcome-MRC Cambridge Stem Cell Institute Date and Time: 8 December, 2023 at 2:45pm PST NOTES TO EDITORS About STORM Therapeutics STORM Therapeutics (STORM) is a clinical stage biotechnology company creating novel therapies that inhibit RNA modifying enzymes (RME) for use in oncology and other diseases. There are more than 150 RNA modifications reported and approximately 300 RNA modifying enzymes which represent novel therapeutic targets. STORM has leveraged its first-mover advantage to establish a novel drug discovery and RNA analytics platform leading to the identification of novel targets and a proprietary pipeline of first-in-class small-molecule drug candidates for potential use in oncology, inflammation, viral infection and CNS diseases. The pipeline is exemplified by STORM's METTL3 inhibitor, STC-15, which has received IND approval and commenced its Phase 1 clinical study in cancer patients in November 2022. STC-15 represents the first ever RNA modifying enzyme inhibitor to enter clinical evaluation in humans. Additional programs are planned for advancement into IND-track activities in 2023. STORM investors include M Ventures, Pfizer Ventures, Taiho Ventures LLC, Seroba Life Sciences, Cambridge Innovation Capital I Limited, IP Group plc, UTokyo Innovation Platform Co., Ltd. (UTokyo IPC) and the Fast Track Initiative (FTI). For more information, please visit . About STC-15 STORM's lead clinical program STC-15 is a first-in-class inhibitor of RNA modification and is the first ever RNA methyltransferase inhibitor to enter clinical development. STC-15 is an oral small molecule that inhibits METTL3, an RNA methyltransferase implicated in oncology and other diseases. Certain RNA methyltransferases are important regulators of RNA sensing and innate immune activation and represent novel immune-regulatory targets. STC-15 has also been shown preclinically to inhibit tumour growth through mechanisms involving anti-cancer immune responses, such as changes in interferon signalling and synergy with T cell checkpoint blockade. STORM commenced the dosing of the first patient in a Phase 1 clinical study of STC-15 in patients living with solid tumours in November 2022 and anticipates presenting first results from its study in 2024. Details of the study can be found on clinicaltrials.gov under the identifier NCT05584111. About the Cambridge Stem Cell Institute The Wellcome-MRC Cambridge Stem Cell Institute (CSCI) is a world-leading centre for stem cell research with a mission to transform human health through a deep understanding of normal and pathological stem cell behaviour. Bringing together biological, clinical and physical scientists operating across a range of tissue types and at multiple scales, we explore the commonalities and differences in stem cell biology in a cohesive and inter-disciplinary manner. Located in a purpose-built facility on the Cambridge Biomedical Campus and housing over 350 researchers, including a critical mass of clinician scientists, the Institute integrates with neighbouring disease-focused research institutes and also serves as a hub for the wider stem cell community in Cambridge. SOURCE STORM Therapeutics