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CANCER DRUG DISCOVERY

Mining for METTL3 inhibitors to suppress cancer

Nature Structural & Molecular Biology volume 28, pages 460–462 (2021)Cite this article

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The RNA methyltransferase METTL3 catalyzes N6-methyladenosine (m6A) modification of messenger RNAs (mRNAs). It is overexpressed in many types of cancer, including acute myelogenous leukemia (AML), and promotes cancer cell growth and tumorigenicity. Now, a selective small molecule inhibitor of METTL3 shows significant antileukemic effects in preclinical AML models, highlighting the promise of pharmacological METTL3 inhibition as a new cancer therapy.

While the importance of DNA methylation and histone modification in gene regulation is well established and chromatin-associated proteins are the subject of current drug development efforts to treat cancer and other diseases1, RNA modifications are less well understood and appreciated. m6A is the most prevalent mRNA modification. It occurs at a particular sequence motif and is enriched at sites close to the translation stop codon in a large subset of the transcriptome2,3. A protein complex comprising METTL3 (methyltransferase-like 3) together with its essential cofactor METTL14 and accessory proteins is responsible for the deposition of almost all m6A on mRNA. The m6A ‘epitranscriptome’ plays important roles in the post-transcriptional control of gene expression, including mRNA splicing, nuclear export, stability and translation4.

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Fig. 1: METTL3 inhibition is a promising therapy against AML.

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Acknowledgements

R.I.G. is supported by an Outstanding Investigator Award (R35CA232115) and R01 grant (R01CA233671) from the National Cancer Institute (NCI) of the NIH.

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Authors and Affiliations

  1. Stem Cell Program, Division of Hematology/Oncology, Boston Children’s Hospital, Boston, MA, USA

    Jiazhi Li & Richard I. Gregory

  2. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA

    Jiazhi Li & Richard I. Gregory

  3. Department of Pediatrics, Harvard Medical School, Boston, MA, USA

    Richard I. Gregory

  4. Harvard Stem Cell Institute, Cambridge, MA, USA

    Richard I. Gregory

  5. Harvard Initiative for RNA Medicine, Boston, MA, USA

    Richard I. Gregory

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  1. Jiazhi Li
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  2. Richard I. Gregory
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J.L. and R.I.G. wrote the manuscript.

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Correspondence to Richard I. Gregory.

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Competing interests

R.I.G. is a cofounder and scientific advisory board member of 28-7 Therapeutics and Theon Therapeutics.

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Li, J., Gregory, R.I. Mining for METTL3 inhibitors to suppress cancer. Nat Struct Mol Biol 28, 460–462 (2021). https://doi.org/10.1038/s41594-021-00606-5

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  • DOI: https://doi.org/10.1038/s41594-021-00606-5

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