Open AccessSmall-molecule inhibition of METTL3 as a strategy against myeloid leukaemia
Author(s) -
Eliza Yankova,
Wesley Blackaby,
Mark R. Albertella,
Justyna Rak,
Étienne De Braekeleer,
Georgia Tsagkogeorga,
E.S. Pilka,
Demetrios Aspris,
Dan Leggate,
Alan G. Hendrick,
Natalie A. Webster,
Byron Andrews,
Richard Fosbeary,
Patrick Guest,
Nerea Irigoyen,
Maria Eleftheriou,
Malgorzata Gozdecka,
João M. L. Dias,
Andrew J. Bannister,
Binje Vick,
Irmela Jeremias,
George S. Vassiliou,
Oliver Rausch,
Konstantinos Tzelepis,
Tony Kouzarides
Publication year - 2021
Publication title -
nature
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 15.993
H-Index - 1226
eISSN - 1476-4687
pISSN - 0028-0836
DOI - 10.1038/s41586-021-03536-w
Subject(s) - cancer research , methyltransferase , in vivo , rna , myeloid leukemia , biology , chemistry , microbiology and biotechnology , biochemistry , gene , genetics , methylation
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.