GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE302nnn/GSE302571/primaryOK200GenomicsMus musculusNon-coding RNA profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE302571GEOGSEfalsePharmacological inhibition of METTL1 as a therapy against solid and haematological cancers [mim-tRNA-Seq]The N7-methylguanosine (m7G) modification is one of the most prevalent modifications on tRNA, mainly catalysed by the METTL1-WDR4 protein complex. The m7G methyltranferase 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 cellular 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.2026/08/12GSE302571GSM9106336GSM9106335GSM9106346GSM9106345GSM9106344GSM9106343GSM9106342GSM9106341GSM9106340GSM9106339GSM9106338GSM910633730172302571Mus musculus