2. Academic Validation
  3. Small-molecule inhibition of METTL3 as a strategy against myeloid leukaemia

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

  • Nature. 2021 May;593(7860):597-601. doi: 10.1038/s41586-021-03536-w.
Eliza Yankova  # 1 2 3,  Wesley Blackaby  # 3,  Mark Albertella 3,  Justyna Rak 2 4,  Etienne De Braekeleer 2 4,  Georgia Tsagkogeorga 1 3,  Ewa S Pilka 5,  Demetrios Aspris 2 6,  Dan Leggate 3,  Alan G Hendrick 3,  Natalie A Webster 3,  Byron Andrews 3,  Richard Fosbeary 3,  Patrick Guest 3,  Nerea Irigoyen 7,  Maria Eleftheriou 1,  Malgorzata Gozdecka 2,  Joao M L Dias 8,  Andrew J Bannister 9,  Binje Vick 10 11,  Irmela Jeremias 10 11 12,  George S Vassiliou 2 4 6,  Oliver Rausch 13,  Konstantinos Tzelepis 14 15 16 17,  Tony Kouzarides 18 19
Affiliations

Affiliations

  • 1 Milner Therapeutics Institute, University of Cambridge, Cambridge, UK.
  • 2 Haematological Cancer Genetics, Wellcome Trust Sanger Institute, Cambridge, UK.
  • 3 Storm Therapeutics Ltd, Cambridge, UK.
  • 4 Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK.
  • 5 Evotec (UK) Ltd, Abingdon, UK.
  • 6 The Center for the Study of Hematological Malignancies/Karaiskakio Foundation, Nicosia, Cyprus.
  • 7 Division of Virology, Department of Pathology, University of Cambridge, Cambridge, UK.
  • 8 MRC Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Cambridge, UK.
  • 9 The Gurdon Institute and Department of Pathology, University of Cambridge, Cambridge, UK.
  • 10 Research Unit Apoptosis in Hematopoietic Stem Cells, Helmholtz Zentrum München, German Research Center for Environmental Health (HMGU), Munich, Germany.
  • 11 German Consortium for Translational Cancer Research (DKTK), Munich, Germany.
  • 12 Department of Pediatrics, Dr. von Hauner Children's Hospital, Ludwig Maximilians University München, Munich, Germany.
  • 13 Storm Therapeutics Ltd, Cambridge, UK. oliver.rausch@stormtherapeutics.com.
  • 14 Milner Therapeutics Institute, University of Cambridge, Cambridge, UK. kt404@cam.ac.uk.
  • 15 Haematological Cancer Genetics, Wellcome Trust Sanger Institute, Cambridge, UK. kt404@cam.ac.uk.
  • 16 Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK. kt404@cam.ac.uk.
  • 17 The Gurdon Institute and Department of Pathology, University of Cambridge, Cambridge, UK. kt404@cam.ac.uk.
  • 18 Milner Therapeutics Institute, University of Cambridge, Cambridge, UK. t.kouzarides@gurdon.cam.ac.uk.
  • 19 The Gurdon Institute and Department of Pathology, University of Cambridge, Cambridge, UK. t.kouzarides@gurdon.cam.ac.uk.
  • # Contributed equally.
PMID: 33902106 DOI: 10.1038/s41586-021-03536-w
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.

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