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crystal structure of METTL3/14 in complex with inhibitor

Tony Kouzarides and colleagues at STORM Therapeutics and the Milner Therapeutics Institute have identified a drug-like molecule that can inhibit an enzyme, METTL3, that plays a key role in the blood cancer, acute myeloid leukaemia. METTL3 is an RNA-modifying enzyme, and this study is the first time an RNA-modification pathway has been targeted as a strategy to fight cancer.

Read the press release from the University of Cambridge and watch Tony tell the story in his video below!

 

Small molecule inhibition of METTL3 as a therapeutic strategy for acute myeloid leukaemia

Yankova, E, et al. Nature; 26 Apr 2021; DOI: 10.1038/s41586-021-03536-w.

Abstract from the paper

The N6-methyladenosine (m6A) is an abundant internal RNA modification catalysed predominantly by the METTL3–METTL14 methyltransferase complex. The m6A writer METTL3 has been linked to the initiation and maintenance of acute myeloid leukaemia (AML), but its true therapeutic importance is still unknown.

Here we present the identification and characterisation of a METTL3 inhibitor (STM2457) along with a co-crystal with the METTL3 enzyme. We demonstrate that this highly potent and selective first-in-class catalytic inhibitor of METTL3 is effective as a new therapeutic strategy against AML. Inhibition of METTL3 in AML cells leads to a reduction in cell growth, and an increase in differentiation and apoptosis. These cellular effects are accompanied by selective reduction of m6A 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 a variety of primary AML models, 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 new avenue for anti-cancer therapy.

 

Image above shows the crystal structure of METTL3/14 in complex with the STM2457 inhibitor   

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Read more about research in the Kouzarides lab.

Watch Tony Kouzarides describe his research on YouTube.

Milner Therapeutics Institute

STORM Therapeutics

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