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

Yankova, Eliza ; Blackaby, Wesley ; Albertella, Mark ; Rak, Justyna ; De Braekeleer, Etienne ; Tsagkogeorga, Georgia ; Pilka, Ewa S ; Aspris, Demetrios ; Leggate, Dan ; Hendrick, Alan G ; Webster, Natalie A ; Andrews, Byron ; Fosbeary, Richard ; Guest, Patrick ; Irigoyen, Nerea ; Eleftheriou, Maria ; Gozdecka, Malgorzata ; Dias, Joao M L ; Bannister, Andrew J ; Vick, Binje ; Jeremias, Irmela ; Vassiliou, George S ; Rausch, Oliver ; Tzelepis, Konstantinos ; Kouzarides, Tony

Nature (London), 2021-05, Vol.593 (7860), p.597-601 [Periódico revisado por pares]

England: Nature Publishing Group

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Small-molecule inhibition of METTL3 as a strategy against myeloid leukaemia
Autor: Yankova, Eliza ; Blackaby, Wesley ; Albertella, Mark ; Rak, Justyna ; De Braekeleer, Etienne ; Tsagkogeorga, Georgia ; Pilka, Ewa S ; Aspris, Demetrios ; Leggate, Dan ; Hendrick, Alan G ; Webster, Natalie A ; Andrews, Byron ; Fosbeary, Richard ; Guest, Patrick ; Irigoyen, Nerea ; Eleftheriou, Maria ; Gozdecka, Malgorzata ; Dias, Joao M L ; Bannister, Andrew J ; Vick, Binje ; Jeremias, Irmela ; Vassiliou, George S ; Rausch, Oliver ; Tzelepis, Konstantinos ; Kouzarides, Tony
Assuntos: Acute myeloid leukemia ; Adenosine - analogs & derivatives ; Animal models ; Animals ; Antineoplastic Agents - pharmacology ; Apoptosis ; Binding sites ; Care and treatment ; Cell cycle ; Cell Differentiation ; Cell Line, Tumor ; Crystal structure ; Enzyme inhibitors ; Enzymes ; Female ; Gene Expression Regulation, Leukemic - drug effects ; Genes ; Health aspects ; Humans ; Kinases ; Leukemia ; Leukemia, Myeloid, Acute - drug therapy ; Methyltransferase ; Methyltransferases ; Methyltransferases - antagonists & inhibitors ; Mice ; Mice, Inbred C57BL ; Molecular Structure ; Myelocytic leukemia ; N6-methyladenosine ; Nonlymphoid leukemia ; Physiological aspects ; Proteins ; Stem cells ; Subpopulations ; Therapeutic applications ; Xenograft Model Antitumor Assays
É parte de: Nature (London), 2021-05, Vol.593 (7860), p.597-601
Descrição: N -methyladenosine (m A) is an abundant internal RNA modification that is catalysed predominantly by the METTL3-METTL14 methyltransferase complex . The m 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 . 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 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.
Editor: England: Nature Publishing Group
Idioma: Inglês

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

England: Nature Publishing Group

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