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Targeting protein methylation: from chemical tools to precision medicines

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Abstract

The methylation of proteins is integral to the execution of many important biological functions, including cell signalling and transcriptional regulation. Protein methyltransferases (PMTs) are a large class of enzymes that carry out the addition of methyl marks to a broad range of substrates. PMTs are critical for normal cellular physiology and their dysregulation is frequently observed in human disease. As such, PMTs have emerged as promising therapeutic targets with several inhibitors now in clinical trials for oncology indications. The discovery of chemical inhibitors and antagonists of protein methylation signalling has also profoundly impacted our general understanding of PMT biology and pharmacology. In this review, we present general principles for drugging protein methyltransferases or their downstream effectors containing methyl-binding modules, as well as best-in-class examples of the compounds discovered and their impact both at the bench and in the clinic.

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Acknowledgements

The authors receive supported from a fellowship from the Natural Sciences and Engineering Research Council (DD) and the SGC, a registered charity (number 1097737) that receives funds from AbbVie, Bayer Pharma AG, Boehringer Ingelheim, Canada Foundation for Innovation, Eshelman Institute for Innovation, Genome Canada through Ontario Genomics Institute [OGI-055], Innovative Medicines Initiative (EU/EFPIA) [ULTRA-DD grant no. 115766], Janssen, Merck KGaA, Darmstadt, Germany, MSD, Novartis Pharma AG, Ontario Ministry of Research, Innovation and Science (MRIS), Pfizer, São Paulo Research Foundation—FAPESP, Takeda, and Wellcome [106169/ZZ14/Z]. We thank Dr Peter J Brown for help with the manuscript.

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  1. Structural Genomics Consortium, University of Toronto, Toronto, ON, M5G 1L7, Canada

    David Dilworth & Dalia Barsyte-Lovejoy

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Correspondence to Dalia Barsyte-Lovejoy.

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Dilworth, D., Barsyte-Lovejoy, D. Targeting protein methylation: from chemical tools to precision medicines. Cell. Mol. Life Sci. 76, 2967–2985 (2019). https://doi.org/10.1007/s00018-019-03147-9

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