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Yankova, E.* ; Blackaby, W.* ; Albertella, M.* ; Rak, J.* ; De Braekeleer, E.* ; Tsagkogeorga, G.* ; Pilka, E.S.* ; Aspris, D.* ; Leggate, D.* ; Hendrick, A.G.* ; Webster, N.A.* ; Andrews, B.* ; Fosbeary, R.* ; Guest, P.* ; Irigoyen, N.* ; Eleftheriou, M.* ; Gozdecka, M.* ; Dias, J.M.L.* ; Bannister, A.J.* ; Vick, B. ; Jeremias, I. ; Vassiliou, G.S.* ; Rausch, O.* ; Tzelepis, K.* ; Kouzarides, T.*

Small molecule inhibition of METTL3 as a strategy against myeloid leukaemia.

Nature 593, 597-601 (2021)

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The N⁶-methyladenosine (m⁶A) is an abundant internal RNA modification^1,2 catalysed predominantly by the METTL3-METTL14 methyltransferase complex^3,4. The m⁶A writer METTL3 has been linked to the initiation and maintenance of acute myeloid leukaemia (AML), but its true therapeutic importance is still unknown^5-7. Here we present the identification and characterization of a highly potent and selective first-in-class catalytic inhibitor of METTL3 (STM2457) and its co-crystal structure bound to METTL3/METTL14. Treatment with STM2457 leads to reduced AML growth, and an increase in differentiation and apoptosis. These cellular effects are accompanied by selective reduction of m⁶A levels on known leukaemogenic mRNAs and a decrease in their expression consistent with a translational defect. We demonstrate that pharmacological inhibition of METTL3 in vivo leads to impaired engraftment and prolonged survival in various AML mouse models, specifically targeting key stem-cell subpopulations of AML. Collectively, these results reveal the inhibition of METTL3 as a potential therapeutic strategy against AML, and provide proof of concept that the targeting of RNA modifying enzymes represents a promising new avenue for anti-cancer therapy.

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