Small-molecule Inhibition of METTL3 As a Strategy Against Myeloid Leukaemia

Overview

Journal Nature

Specialty Science

Date 2021 Apr 26

PMID 33902106

Citations 486

Authors

Eliza Yankova

Wesley Blackaby

Mark Albertella

Justyna Rak

Etienne De 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

Tony Kouzarides

Affiliations

Soon will be listed here.

Abstract

N-methyladenosine (mA) is an abundant internal RNA modification that is catalysed predominantly by the METTL3-METTL14 methyltransferase complex. The mA 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. 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 mA 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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