7o2i
METTL3-METTL14 heterodimer bound to the SAM competitive small molecule inhibitor STM2457
Structural highlights
FunctionMET14_HUMAN N6-methyltransferase that methylates adenosine residues of some mRNAs and acts as a regulator of the circadian clock and differentiation of embryonic stem cells. N6-methyladenosine (m6A), which takes place at the 5'-[AG]GAC-3' consensus sites of some mRNAs, plays a role in the efficiency of mRNA splicing, processing and mRNA stability (PubMed:24316715, PubMed:24407421, PubMed:25719671). M6A regulates the length of the circadian clock: acts as a early pace-setter in the circadian loop. M6A also acts as a regulator of mRNA stability: in embryonic stem cells (ESCs), m6A methylation of mRNAs encoding key naive pluripotency-promoting transcripts results in transcript destabilization (By similarity).[UniProtKB:Q3UIK4][1] [2] [3] Publication Abstract from PubMedN(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. Small-molecule inhibition of METTL3 as a strategy against myeloid leukaemia.,Yankova E, Blackaby W, Albertella M, Rak J, De Braekeleer E, Tsagkogeorga G, Pilka ES, Aspris D, Leggate D, Hendrick AG, Webster NA, Andrews B, Fosbeary R, Guest P, Irigoyen N, Eleftheriou M, Gozdecka M, Dias JML, Bannister AJ, Vick B, Jeremias I, Vassiliou GS, Rausch O, Tzelepis K, Kouzarides T Nature. 2021 May;593(7860):597-601. doi: 10.1038/s41586-021-03536-w. Epub 2021 , Apr 26. PMID:33902106[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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