Abstract
Most protein-coding genes produce multiple protein isoforms; however, these isoforms are commonly neglected in drug discovery. The expression of protein isoforms can be specific to a disease, tissue and/or developmental stage, and this specific expression can be harnessed to achieve greater drug specificity than pan-targeting of all gene products and to enable improved treatments for diseases caused by aberrant protein isoform production. In recent years, several protein isoform-centric therapeutics have been developed. Here, we collate these studies and clinical trials to highlight three distinct but overlapping modes of action for protein isoform-centric drugs: isoform switching, isoform introduction or depletion, and modulation of isoform activity. In addition, we discuss how protein isoforms can be used clinically as targets for cell type-specific drug delivery and immunotherapy, diagnostic biomarkers and sources of cancer neoantigens. Collectively, we emphasize the value of a focus on isoforms as a route to discovering drugs with greater specificity and fewer adverse effects. This approach could enable the targeting of proteins for which pan-inhibition of all isoforms is toxic and poorly tolerated.
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Acknowledgements
The authors acknowledge the members of the Weatheritt lab for fruitful discussions on protein isoforms and their therapeutic uses. They also thank S. Zinn, D. Christ and A. Cooper, for critical reading of the manuscript and helpful suggestions. They thank A. Grootveld for discussions on vaccination responses and P. Sinitcyn for discussions on using mass spectrometry for protein isoform characterization. P.K.-H. discloses support for this work from a University International Postgraduate Award scholarship from the University of New South Wales and a Peter & Emma Thomsens legat (stipend). T.G.P. is supported by the Australian National Health and Medical Research Council (NHMRC) Investigator Grant (APPID1155678), the Kinghorn Foundation, Cancer Institute NSW, Australian Cancer Research Foundation and the Tour de Cure. R.J.W. discloses support for this work from E. P. Oldham — Viertel Senior Medical Fellowship, the Scrimshaw Family Foundation, EMBL Australia, Australian Research Council Future Fellowship and Discovery Project, NSW Institute of Cancer Research and NSW Cancer Council.
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Kjer-Hansen, P., Phan, T.G. & Weatheritt, R.J. Protein isoform-centric therapeutics: expanding targets and increasing specificity. Nat Rev Drug Discov 23, 759–779 (2024). https://doi.org/10.1038/s41573-024-01025-z
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DOI: https://doi.org/10.1038/s41573-024-01025-z
