Genome-wide transcriptomic and m6A profiling of MOLM13 cells treated with vehicle or small molecule inhibitor of METTL3

The N6-methyladenosine (m6A) is an abundant internal RNA modification catalysed predominantly by the METTL3–METTL14 methyltransferase complex. The m6A writer METTL3, has been linked to the initiation and maintenance of aggressive cancers including acute myeloid leukaemia (AML). However, its true therapeutic importance is still unknown to date. Here we present the development and characterisation of the first-in-class catalytic inhibitor of METTL3 using a bioavailable small molecule (STM2457) as a new therapeutic strategy for AML. We confirm that STM2457 is a highly potent and specific inhibitor of METTL3 catalytic activity. Pharmacological inhibition of METTL3 leads to significant reduction in cell growth, increased differentiation and apoptosis in human and murine AMLs accompanied with selective reduction of m6A levels on known leukaemogenic mRNA substrates. Transcriptomic and m6A profiling reveals that catalytic inhibition of METTL3 effects key oncogenic pathways via mRNA translational defects. We provide evidence that pharmacological inhibition of METTL3 in vivo leads to impaired engraftment and prolonged survival of a variety of primary AML models. We also show that STM2457 negatively effects the levels of key leukaemic stem cells. Collectively, our work reveals for the first time the potential of pharmacological inhibition of METTL3 as a novel therapeutic strategy against AML.