Small-molecule inhibition of METTL3 as a strategy against myeloid leukaemia
Authors: Patrick Guest
Irmela Jeremias
Maria Eleftheriou
Konstantinos Tzelepis
Eliza Yankova
Oliver Rausch
Richard Fosbeary
Andrew J Bannister
Etienne De Braekeleer
George S Vassiliou
Alan G Hendrick
Byron Andrews
Nerea Irigoyen
Malgorzata Gozdecka
Georgia Tsagkogeorga
Demetrios Aspris
Dan Leggate
Joao M L Dias
Mark Albertella
Justyna Rak
Wesley Blackaby
Ewa S Pilka
Binje Vick
Natalie A Webster
Tony Kouzarides
Journal: Nature (2021)
Discipline: Multidisciplinary
Keywords: N6-methyladenosine; RNA modification; METTL3; METTL14; STM2457
Affiliations: Milner Therapeutics Institute, University of Cambridge, Cambridge, UK., Haematological Cancer Genetics, Wellcome Trust Sanger Institute, Cambridge, UK., Storm Therapeutics Ltd, Cambridge, UK., Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK., Evotec (UK) Ltd, Abingdon, UK., The Center for the Study of Hematological Malignancies/Karaiskakio Foundation, Nicosia, Cyprus., Division of Virology, Department of Pathology, University of Cambridge, Cambridge, UK., MRC Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Cambridge, UK., The Gurdon Institute and Department of Pathology, University of Cambridge, Cambridge, UK., Research Unit Apoptosis in Hematopoietic Stem Cells, Helmholtz Zentrum München, German Research Center for Environmental Health (HMGU), Munich, Germany., German Consortium for Translational Cancer Research (DKTK), Munich, Germany., Department of Pediatrics, Dr. von Hauner Children's Hospital, Ludwig Maximilians University München, Munich, Germany., Storm Therapeutics Ltd, Cambridge, UK. ., Milner Therapeutics Institute, University of Cambridge, Cambridge, UK. ., Haematological Cancer Genetics, Wellcome Trust Sanger Institute, Cambridge, UK. ., Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK. ., The Gurdon Institute and Department of Pathology, University of Cambridge, Cambridge, UK. .

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. 

Retracted: No

PubPeer comments:
 Figure 2e: ![file] There appear to be some very similar patterns in the vehicle graphs for MLL-AF9 Flt3ltd + and HPC7 (marked as rectangles) and between the vehicle graph for MOLM13 and the SM2457 graph for HPC7 (marked as circles ellipsoids). These are all supposed to be different cell types, different conditions - could there have been a mixup? , 
 I don t know if this impacts the conclusions of the paper, but some FACS plots look like they have been duplicated. ![file] , 
 I agree. The highlighted plots look more similar then expected. I am not a FACS expert but, at higher magnifications, it seems that some data points have been removed. Compare for instance the rightmost side of the plot in MOLM-13 Vehicle vs. HPC7 SM2457. ,