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

Autor: Yankova E; Milner Therapeutics Institute, University of Cambridge, Cambridge, UK.; Haematological Cancer Genetics, Wellcome Trust Sanger Institute, Cambridge, UK.; Storm Therapeutics Ltd, Cambridge, UK., Blackaby W; Storm Therapeutics Ltd, Cambridge, UK., Albertella M; Storm Therapeutics Ltd, Cambridge, UK., Rak J; Haematological Cancer Genetics, Wellcome Trust Sanger Institute, Cambridge, UK.; Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK., De Braekeleer E; Haematological Cancer Genetics, Wellcome Trust Sanger Institute, Cambridge, UK.; Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK., Tsagkogeorga G; Milner Therapeutics Institute, University of Cambridge, Cambridge, UK.; Storm Therapeutics Ltd, Cambridge, UK., Pilka ES; Evotec (UK) Ltd, Abingdon, UK., Aspris D; Haematological Cancer Genetics, Wellcome Trust Sanger Institute, Cambridge, UK.; The Center for the Study of Hematological Malignancies/Karaiskakio Foundation, Nicosia, Cyprus., Leggate D; Storm Therapeutics Ltd, Cambridge, UK., Hendrick AG; Storm Therapeutics Ltd, Cambridge, UK., Webster NA; Storm Therapeutics Ltd, Cambridge, UK., Andrews B; Storm Therapeutics Ltd, Cambridge, UK., Fosbeary R; Storm Therapeutics Ltd, Cambridge, UK., Guest P; Storm Therapeutics Ltd, Cambridge, UK., Irigoyen N; Division of Virology, Department of Pathology, University of Cambridge, Cambridge, UK., Eleftheriou M; Milner Therapeutics Institute, University of Cambridge, Cambridge, UK., Gozdecka M; Haematological Cancer Genetics, Wellcome Trust Sanger Institute, Cambridge, UK., Dias JML; MRC Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Cambridge, UK., Bannister AJ; The Gurdon Institute and Department of Pathology, University of Cambridge, Cambridge, UK., Vick B; 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., Jeremias I; 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., Vassiliou GS; Haematological Cancer Genetics, Wellcome Trust Sanger Institute, Cambridge, UK.; Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK.; The Center for the Study of Hematological Malignancies/Karaiskakio Foundation, Nicosia, Cyprus., Rausch O; Storm Therapeutics Ltd, Cambridge, UK. oliver.rausch@stormtherapeutics.com., Tzelepis K; Milner Therapeutics Institute, University of Cambridge, Cambridge, UK. kt404@cam.ac.uk.; Haematological Cancer Genetics, Wellcome Trust Sanger Institute, Cambridge, UK. kt404@cam.ac.uk.; Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK. kt404@cam.ac.uk.; The Gurdon Institute and Department of Pathology, University of Cambridge, Cambridge, UK. kt404@cam.ac.uk., Kouzarides T; Milner Therapeutics Institute, University of Cambridge, Cambridge, UK. t.kouzarides@gurdon.cam.ac.uk.; The Gurdon Institute and Department of Pathology, University of Cambridge, Cambridge, UK. t.kouzarides@gurdon.cam.ac.uk.
Jazyk: angličtina
Zdroj: Nature [Nature] 2021 May; Vol. 593 (7860), pp. 597-601. Date of Electronic Publication: 2021 Apr 26.
DOI: 10.1038/s41586-021-03536-w
Abstrakt: N 6 -methyladenosine (m 6 A) is an abundant internal RNA modification 1,2 that is catalysed predominantly by the METTL3-METTL14 methyltransferase complex 3,4 . The m 6 A 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 unknown 5-7 . 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 m 6 A 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.
Databáze: MEDLINE
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