The PROTACtable genome

• Published in: Nature reviews. Drug discovery Vol. 20; no. 10; pp. 789 - 797
• Main Authors: Schneider, Melanie, Radoux, Chris J., Hercules, Andrew, Ochoa, David, Dunham, Ian, Zalmas, Lykourgos-Panagiotis, Hessler, Gerhard, Ruf, Sven, Shanmugasundaram, Veerabahu, Hann, Michael M., Thomas, Pam J., Queisser, Markus A., Benowitz, Andrew B., Brown, Kris, Leach, Andrew R.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.10.2021; Nature Publishing Group
• Subjects: 631/114/2164; 631/154/555; Animals; Biomedical and Life Sciences; Biomedicine; Biotechnology; Cancer Research; Decision making; Drug Design; Drug targeting; Forecasts and trends; Genome; Genomes; Health aspects; Humans; Medicinal Chemistry; Molecular Medicine; Perspective; Pharmacology/Toxicology; Precision medicine; Proteins; Proteolysis; Research Design; Small Molecule Libraries; United States; United Kingdom
• ISSN: 1474-1776; 1474-1784
• DOI: 10.1038/s41573-021-00245-x

Proteolysis-targeting chimeras (PROTACs) are an emerging drug modality that may offer new opportunities to circumvent some of the limitations associated with traditional small-molecule therapeutics. By analogy with the concept of the ‘druggable genome’, the question arises as to which potential drug targets might PROTAC-mediated protein degradation be most applicable. Here, we present a systematic approach to the assessment of the PROTAC tractability (PROTACtability) of protein targets using a series of criteria based on data and information from a diverse range of relevant publicly available resources. Our approach could support decision-making on whether or not a particular target may be amenable to modulation using a PROTAC. Using our approach, we identified 1,067 proteins of the human proteome that have not yet been described in the literature as PROTAC targets that offer potential opportunities for future PROTAC-based efforts. Targeted protein degradation by proteolysis-targeting chimeras (PROTACs) is attracting substantial interest as a therapeutic modality that could circumvent some limitations of traditional small-molecule drugs. This article presents a systematic approach to assessing the PROTAC tractability (PROTACtability) of protein targets, which could support decision-making on whether a particular target may be amenable to modulation using a PROTAC.