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Life sciences · Journal article
Nature · October 28, 2026
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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.