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

Eliza Yankova, Wesley Blackaby, Mark Albertella, Justyna Rak, Etienne Braekeleer, Georgia Tsagkogeorga, Ewa S. Pilka, Demetrios Aspris, Dan Leggate, Alan G. Hendrick, Natalie A. Webster, Byron Andrews, Richard Fosbeary, Patrick Guest, Nerea Irigoyen, Maria Eleftheriou, Malgorzata Gozdecka, Joao M. L. Dias, Andrew J. Bannister, Binje Vick, Irmela Jeremias, George S. Vassiliou, Oliver Rausch (), Konstantinos Tzelepis () and Tony Kouzarides ()
Additional contact information
Eliza Yankova: University of Cambridge
Wesley Blackaby: Storm Therapeutics Ltd
Mark Albertella: Storm Therapeutics Ltd
Justyna Rak: Wellcome Trust Sanger Institute
Etienne Braekeleer: Wellcome Trust Sanger Institute
Georgia Tsagkogeorga: University of Cambridge
Ewa S. Pilka: Evotec (UK) Ltd
Demetrios Aspris: Wellcome Trust Sanger Institute
Dan Leggate: Storm Therapeutics Ltd
Alan G. Hendrick: Storm Therapeutics Ltd
Natalie A. Webster: Storm Therapeutics Ltd
Byron Andrews: Storm Therapeutics Ltd
Richard Fosbeary: Storm Therapeutics Ltd
Patrick Guest: Storm Therapeutics Ltd
Nerea Irigoyen: University of Cambridge
Maria Eleftheriou: University of Cambridge
Malgorzata Gozdecka: Wellcome Trust Sanger Institute
Joao M. L. Dias: Hutchison/MRC Research Centre
Andrew J. Bannister: University of Cambridge
Binje Vick: Helmholtz Zentrum München, German Research Center for Environmental Health (HMGU)
Irmela Jeremias: Helmholtz Zentrum München, German Research Center for Environmental Health (HMGU)
George S. Vassiliou: Wellcome Trust Sanger Institute
Oliver Rausch: Storm Therapeutics Ltd
Konstantinos Tzelepis: University of Cambridge
Tony Kouzarides: University of Cambridge

Nature, 2021, vol. 593, issue 7860, 597-601

Abstract: Abstract N6-methyladenosine (m6A) is an abundant internal RNA modification1,2 that is catalysed predominantly by the METTL3–METTL14 methyltransferase complex3,4. The m6A methyltransferase METTL3 has been linked to the initiation and maintenance of acute myeloid leukaemia (AML), but the potential of therapeutic applications targeting this enzyme remains unknown5–7. Here we present the identification and characterization of STM2457, a highly potent and selective first-in-class catalytic inhibitor of METTL3, and a crystal structure of STM2457 in complex with METTL3–METTL14. Treatment of tumours 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 mouse models of AML, 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 avenue for anticancer therapy.

Date: 2021
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DOI: 10.1038/s41586-021-03536-w

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