Pharmacological inhibition of METTL1 as a therapy against solid and blood cancers
Abstract The N7-methylguanosine (m 7 G) modification is one of the most prevalent tRNA modifications, mainly catalysed by the METTL1–WDR4 protein complex 1–4 . The m 7 G methyltransferase METTL1 has been linked to oncogenic transformation and the maintenance of several aggressive malignancies; however, the clinical implications of therapeutically targeting a tRNA-modifying enzyme have not been established. Here we present the development and characterization of STM9005, a highly selective and potent first-in-class tRNA methyltransferase inhibitor of METTL1. Treatment of numerous cancer cell models (including leukaemia, melanoma, pancreatic carcinoma, oesophageal cancer and small cell lung carcinoma) with STM9005 blocks cell growth, causes differentiation changes and dysregulates cell cycle progression. These cellular effects were accompanied by a selective decrease in m 7 G on a subset of tRNAs and a reduction in their expression levels, which impacted the translation of oncogenic mRNAs. We show that pharmacological inhibition of METTL1 in vivo impairs tumour growth and significantly prolongs survival in multiple mouse cancer models of different tissue origin. Collectively, our results provide a strong proof of concept that targeting of tRNA methylation is a promising avenue of anti-cancer therapy and illustrate that catalytic inhibition of METTL1 represents a therapeutic strategy against a number of aggressive malignancies.
Authors
- Konstantinos Tzelepis (ORCID: https://orcid.org/0000-0002-4865-7648)
- Giovanna Mantica (ORCID: https://orcid.org/0000-0002-7429-7236)
- Fotios Sampaziotis (ORCID: https://orcid.org/0000-0003-0812-7586)
- Malgorzata Gozdecka (ORCID: https://orcid.org/0000-0002-3134-1276)
- Teresa Brevini (ORCID: https://orcid.org/0000-0002-3581-5379)
- Alexandra Sapetschnig (ORCID: https://orcid.org/0000-0001-8617-0235)
- Judith López (ORCID: https://orcid.org/0000-0003-3202-9935)
- Maria Pilar Alcolea (ORCID: https://orcid.org/0000-0002-8396-6454)
- George Giotopoulos (ORCID: https://orcid.org/0000-0003-1390-6592)
- George S. Vassiliou (ORCID: https://orcid.org/0000-0003-4337-8022)
- Andrew Hutchin (ORCID: https://orcid.org/0000-0002-4961-6995)
- Brian J.P. Huntly (ORCID: https://orcid.org/0000-0003-0312-161X)
- Byron Andrews (ORCID: https://orcid.org/0009-0000-5684-9685)
- Aleksandra Azevedo (ORCID: https://orcid.org/0009-0007-2280-9483)
- Richard Fosbeary
- Rachael Wilson (ORCID: https://orcid.org/0000-0001-5129-7295)
- Maria Teresa Béjar (ORCID: https://orcid.org/0000-0002-8850-0178)
- Walid T. Khaled (ORCID: https://orcid.org/0000-0001-9068-5776)
- Oliver Rausch (ORCID: https://orcid.org/0000-0003-4074-3848)
- Natalie A. Webster (ORCID: https://orcid.org/0000-0003-4973-434X)
- Eliza Yankova (ORCID: https://orcid.org/0000-0003-2913-0012)
- Carmen Maria Livi (ORCID: https://orcid.org/0000-0002-4974-1403)
- S.J. Bucknell (ORCID: https://orcid.org/0000-0002-6501-8899)
- Jack F. Rogan
- Yogeshkumar Malam (ORCID: https://orcid.org/0000-0002-1192-7560)
- Beth Ann Thomas
- Roland Rad (ORCID: https://orcid.org/0000-0002-6849-9659)
- Hendrik Weisser (ORCID: https://orcid.org/0000-0001-9723-7503)
- Dean C. Pask
- Elisa Laurenti (ORCID: https://orcid.org/0000-0002-9917-9092)
- Jake Tobin (ORCID: https://orcid.org/0009-0001-2939-0896)
- Sunay Usluer (ORCID: https://orcid.org/0000-0002-2630-3865)
- Harry Fischl (ORCID: https://orcid.org/0000-0002-8727-5917)
- Evangelia Stamou
- Maria Eleftheriou (ORCID: https://orcid.org/0000-0002-1842-5838)
- Sapphire Sawyer (ORCID: https://orcid.org/0009-0008-9281-1666)
- David J. Adams (ORCID: https://orcid.org/0000-0001-9490-0306)
- Vidur Tandon (ORCID: https://orcid.org/0009-0001-4787-7825)
- Nithila Joseph (ORCID: https://orcid.org/0000-0002-6462-8660)
- Ryan Asby
- Siân Evans
- Joanna Baxter
- Laura Bond
- James Russell
- Juan Li
- Diego Lopez-Leon
Institutions
- AstraZeneca (United Kingdom) (GB)
- NHS Blood and Transplant (GB)
- Wellcome/MRC Cambridge Stem Cell Institute (GB)
- University of Cambridge (GB)
- Cambridge University Hospitals NHS Foundation Trust (GB)
- Wellcome Sanger Institute (GB)
- TUM Klinikum (DE)
- Open Targets (GB)
- Evotec (United Kingdom) (GB)
- Deutsches Konsortium für Translationale Krebsforschung (DE)
- Technical University of Munich (DE)
Publication Details
- Journal
- Nature
- Published
- 2026-10-28
- DOI
- https://doi.org/10.1038/s41586-026-11178-z
- Primary Topic
- RNA modifications and cancer
- Type
- article
- Field-Weighted Citation Impact
- 0.00