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Pharmacological inhibition of METTL1 as a novel anti-cancer strategy

ABSTRACT: The N7-methylguanosine (m7G) modification is one of the most prevalent modifications on tRNA, mainly catalysed by the METTL1-WDR4 protein complex1-4. The m7G methyltransferase METTL1 has been connected to oncogenic transformation and maintenance of several aggressive malignancies but the impact of a therapeutic targeting a tRNA-modifying enzyme is yet to be determined. Here, we present the development and characterisation of STM9005, a highly selective and potent first-in-class tRNA methyltransferase inhibitor of METTL1. Treatment of numerous tumour models with STM9005 reduces cancer growth, causes differentiation changes and dysregulates cell cycle progression. These cellular effects were accompanied by a selective decrease of m7G on a subset of tRNAs and a reduction in their expression levels, which led to an impact on oncogenic mRNA translation. We illustrate that pharmacological inhibition of METTL1 in vivo impairs tumour growth and leads to a significant prolongation of survival in various mouse cancer models of different tissue origin. Collectively, our results provide strong proof-of-concept that targeting of tRNA methylation is a novel avenue of anti-cancer therapy, and illustrate that catalytic inhibition of METTL1 represents a novel therapeutic strategy against a number of aggressive malignancies.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE303386 | GEO | 2026/08/17

REPOSITORIES: GEO

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