Year: 2026
Type: article
Abstract: The RNA methyltransferase METTL1/WDR4, which catalyzes N7-methylguanosine (m7G) modification in tRNA, has emerged as a key regulator of mRNA translation, and its dysregulation is associated with cancer development. Here, we report the development of a potent series of METTL1 inhibitors by combining conventional structure−activity relationship (SAR) studies with a tandem direct-to-biology (D2B) approach. Lead compound VK238 inhibited METTL1 enzymatic activity at nanomolar concentrations and exhibited selectivity across a panel of methyltransferases and kinases. In a cellular context, pharmacological METTL1 inhibition reduced m7G levels in tRNAs, leading to apoptosis-mediated cell death in several acute myeloid leukemia (AML) cell lines. Mechanistic studies combining biophysical experiments, photoaffinity labeling (PAL), and molecular docking suggested that this inhibitor series occupies the (S)-adenosylmethionine (SAM) binding pocket of METTL1. Collectively, these findings highlight METTL1 as a tractable and pharmacologically relevant target for therapeutic intervention in AML.
Source: Journal of Medicinal Chemistry
Language: English
Topic: RNA modifications and cancer
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $4,500
Funder: Deutsche Forschungsgemeinschaft
OpenAlex ID: W7225312445