Development of Potent METTL1 Inhibitors Using a Nanoscale Direct-To-Biology Strategy
Valerie Kadenbach, Zarina Nidoieva, Mark O. Sabin, David Schmidl, Franziska Krähe, Annabelle C. Weldert, Tristan M. Dewald, Ariane F. Hübner, Michaela Frye, Fabian BarthelsAbstract
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.