The PROTACtable genome
Abstract
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.
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Methods to assess the PROTACtability of POIs have been suggested, prioritizing over a thousand proteins with potential for becoming PROTAC targets.
“For example, methods to assess the PROTACtability of POIs have been suggested,245 prioritizing over a thousand proteins with potential for becoming PROTAC targets.”
From Advancing Targeted Protein Degradation via Multiomics Profiling and Artificial Intelligence (2023) · cites this paper as [245]
Schneider et al. based their analysis on availability of a small-molecule binder, endogenous ubiquitylation status, and target protein half-life.
“They based their analysis on several aspects of protein degradation mentioned here, such as availability of a small-molecule binder against the target, information on the endogenous ubiquitylation status of the target and target protein half-life.”
From PROTAC targeted protein degraders: the past is prologue (2022) · cites this paper as [70]
Schneider et al. provided the first systematic assessment of drug targets according to their ability to be degraded by PROTAC molecules.
“Schneider et al.70 have provided the first systematic assessment of drug targets according to their ability to be degraded by PROTAC molecules.”
From PROTAC targeted protein degraders: the past is prologue (2022) · cites this paper as [70]
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Christiano, R., Arlt, H., Kabatnik, S., et al. (2020) · Cell Reports · doi:10.1016/j.celrep.2020.108378 · Cited by 26 · see citing works
Evolutionary Survey of Druggable Protein Targets with Respect to Their Subcellular Localizations
Wang, X., Wang, R., Zhang, Y., & Zhang, H. (2013) · Genome Biology and Evolution · doi:10.1093/gbe/evt092 · Cited by 21 · see citing works
The Missing Link between (Un)druggable and Degradable KRAS
Vita, E. D., Maneiro, M., & Tate, E. W. (2020) · ACS Central Science · doi:10.1021/acscentsci.0c00920 · Cited by 4 · see citing works
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PROTAC targeted protein degraders: the past is prologue
Békés, M., Langley, D. R., & Crews, C. M. (2022) · Nature Reviews Drug Discovery · doi:10.1038/s41573-021-00371-6 · Cited by 3,395 · see citing works
The next-generation Open Targets Platform: reimagined, redesigned, rebuilt
Ochoa, D., Hercules, A., Carmona, M., Suveges, D., Baker, J., Malangone, C., Lopez, I., Miranda, A., Cruz-Castillo, C., Fumis, L., et al. (2023) · Nucleic Acids Research · doi:10.1093/nar/gkac1046 · Cited by 432 · see citing works
Self-citationBridged Proteolysis Targeting Chimera (PROTAC) Enables Degradation of Undruggable Targets
Xiong, Y., Zhong, Y., Yim, H., Yang, X., Park, K.-S., Xie, L., Poulikakos, P. I., Han, X., Xiong, Y., Chen, X., et al. (2022) · Journal of the American Chemical Society · doi:10.1021/jacs.2c09255 · Cited by 154 · see citing works
PROTAC degraders as chemical probes for studying target biology and target validation
Němec, V., Schwalm, M. P., Müller, S., & Knapp, S. (2022) · Chemical Society Reviews · doi:10.1039/d2cs00478j · Cited by 98 · see citing works
PROTAC therapy as a new targeted therapy for lung cancer
Li, J. W., Zheng, G., Kaye, F. J., & Wu, L. (2023) · Molecular Therapy · doi:10.1016/j.ymthe.2022.11.011 · Cited by 87 · see citing works
Advancing Targeted Protein Degradation via Multiomics Profiling and Artificial Intelligence
Duran-Frigola, M., Cigler, M., & Winter, G. E. (2023) · Journal of the American Chemical Society · doi:10.1021/jacs.2c11098 · Cited by 50 · see citing works
Application of Novel Degraders Employing Autophagy for Expediting Medicinal Research
Li, X., Liu, Q., Xie, X., Peng, C., Pang, Q., Liu, B., & Han, B. (2023) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.2c01712 · Cited by 46 · see citing works
Dixon, T., MacPherson, D., Mostofian, B., Dauzhenka, T., Lotz, S., McGee, D., Shechter, S., Shrestha, U. R., Wiewiora, R., McDargh, Z. A., et al. (2021) · doi:10.1101/2021.09.26.461830 · Cited by 7 · see citing works
- Authors
- Schneider, M., Radoux, C. J., Hercules, A., Ochoa, D., Dunham, I., Zalmas, L.-P., Hessler, G., Ruf, S., Shanmugasundaram, V., Hann, M. M., Thomas, P. J., Queisser, M. A., Benowitz, A. B., Brown, K., & Leach, A. R.
- Affiliations
- European Bioinformatics Institute (GB)
- Wellcome Sanger Institute (GB)
- Sanofi (Germany) (DE)
- Bristol-Myers Squibb (United States) (US)
- GlaxoSmithKline (United Kingdom) (GB)
- Agenus (United States) (US)
- Corresponding author
- Leach, Andrew R.
- ORCID
- Venue
- Nature Reviews Drug Discovery
- Published
- 2021-07-20
- Volume
- 20
- Issue
- 10
- Pages
- 789-797
- ISSN
- 1474-1776 (ISSN-L)
- 1474-1784
- OpenAlex
- W3186493235
- Cited by
- 273
- References
- 89
- Citations by year
- 2026: 35 · 2025: 57 · 2024: 59 · 2023: 38 · 2022: 77 · 2021: 7
- FWCI
- 4.93
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Nature Reviews Drug Discovery (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chemical Synthesis and Analysis
- Keywords
- PROTACs, targeted protein degradation, druggable genome, protein targets, human proteome
- MeSH terms
- Animals, Humans, Research Design, Drug Design, Genome, Small Molecule Libraries
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
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