7O2I

METTL3-METTL14 heterodimer bound to the SAM competitive small molecule inhibitor STM2457

Summary for 7O2I

• Entry DOI: 10.2210/pdb7o2i/pdb
• Descriptor: N6-adenosine-methyltransferase catalytic subunit, N6-adenosine-methyltransferase non-catalytic subunit, ~{N}-[[6-[(cyclohexylmethylamino)methyl]imidazo[1,2-a]pyridin-2-yl]methyl]-4-oxidanylidene-1~{H}-pyrido[1,2-a]pyrimidine-2-carboxamide, ... (5 entities in total)
• Functional Keywords: methyltransferase, sam, inhibitor, m6a, rna binding protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 60175.70

Authors

Pilka, E.S.,Blackaby, W.,Hardick, D.,Harper, C.,Hewstone, D.,Ridgill, M.,Rotty, B.,Rausch, O. (deposition date: 2021-03-30, release date: 2021-04-14, Last modification date: 2024-11-13)

Primary citation

Yankova, E.,Blackaby, W.,Albertella, M.,Rak, J.,De Braekeleer, E.,Tsagkogeorga, G.,Pilka, E.S.,Aspris, D.,Leggate, D.,Hendrick, A.G.,Webster, N.A.,Andrews, B.,Fosbeary, R.,Guest, P.,Irigoyen, N.,Eleftheriou, M.,Gozdecka, M.,Dias, J.M.L.,Bannister, A.J.,Vick, B.,Jeremias, I.,Vassiliou, G.S.,Rausch, O.,Tzelepis, K.,Kouzarides, T.
Small-molecule inhibition of METTL3 as a strategy against myeloid leukaemia.
Nature, 593:597-601, 2021

PubMed 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.

PubMed: 33902106
DOI: 10.1038/s41586-021-03536-w

Experimental method

X-RAY DIFFRACTION (3 Å)