Pharmacological inhibition of METTL1 as a therapy against solid and blood cancers.

STM9005, a selective METTL1 inhibitor, blocks growth and alters differentiation in multiple cancer cell models, with m7G decreases on a subset of tRNAs linked to reduced oncogenic mRNA translation.

• Why it matters: METTL1-driven tRNA N7-methylguanosine (m7G) methylation is linked to oncogenic transformation, but whether pharmacologically targeting this tRNA-modifying enzyme is clinically relevant was unclear.
• What they did: The study developed and characterized STM9005 and treated numerous leukemia, melanoma, pancreatic carcinoma, oesophageal cancer, and small cell lung carcinoma cell models, then assessed m7G levels, tRNA expression, and translation of oncogenic mRNAs.
• The result: Pharmacological METTL1 inhibition in vivo impaired tumour growth and significantly prolonged survival across multiple mouse cancer models from different tissue origins, supporting METTL1 catalytic inhibition as an anti-cancer strategy.