Inhibitors of Protein Methyltransferases as Chemical Tools

Abstract

Protein methyltransferases (PMT)s play essential roles in many biological processes through methylation of histones and diverse nonhistone substrates. Dysregulation of these enzymes has been implicated in many diseases including cancers. While PMT-associated biology can be probed via genetic perturbation, this approach targets full-length PMTs rather than their methyltransferase activities and often lacks temporal, spatial and dose controls (timing, location and amount of dosed compounds). By contrast, small-molecule inhibitors of PMTs can be designed to specifically target the methyltransferase domains in a temporal, spatial and dose-dependent manner. This utility has motivated the development of hundreds of PMT inhibitors, but meanwhile can make it challenging to select the most suitable PMT inhibitors to interrogate PMT-associated biology. This perspective aims to provide timely guidance to evaluate these PMT inhibitors in their relevant biological contexts.

Keywords::

• chemical probe
• MOA
• off-target effects
• PKMT
• PRMT
• target engagement

Acknowledgements

The author would like to thank M Langberg and R Blawski for proof-reading the manuscript.

Financial & competing interest disclosure

The work carried out by the Luo laboratory and discussed in this article received support from NIGMS (1R01GM096056), the NIH Director’s New Innovator Award Program (1DP2-OD007335), NIH/NCI Cancer Center Support Grant 5P30 CA008748-44, Starr Cancer Consortium, WH Goodwin and A Goodwin Commonwealth and the Foundation for Cancer Research, The Experimental Therapeutics Center of Memorial Sloan Kettering Cancer Center, Tri-I Therapeutics Discovery Grant and Sohn Conference Foundation. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Additional information

Funding

The work carried out by the Luo laboratory and discussed in this article received support from NIGMS (1R01GM096056), the NIH Director’s New Innovator Award Program (1DP2-OD007335), NIH/NCI Cancer Center Support Grant 5P30 CA008748-44, Starr Cancer Consortium, WH Goodwin and A Goodwin Commonwealth and the Foundation for Cancer Research, The Experimental Therapeutics Center of Memorial Sloan Kettering Cancer Center, Tri-I Therapeutics Discovery Grant and Sohn Conference Foundation. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.