Development of Protacs to Target Cancer-promoting Proteins for Ubiquitination and Degradation
Open accessAbstract
The proteome contains hundreds of proteins that in theory could be excellent therapeutic targets for the treatment of human diseases. However, many of these proteins are from functional classes that have never been validated as viable candidates for the development of small molecule inhibitors. Thus, to exploit fully the potential of the Human Genome Project to advance human medicine, there is a need to develop generic methods of inhibiting protein activity that do not rely on the target protein's function. We previously demonstrated that a normally stable protein, methionine aminopeptidase-2 or MetAP-2, could be artificially targeted to an Skp1-Cullin-F-box (SCF) ubiquitin ligase complex for ubiquitination and degradation through a chimeric bridging molecule or Protac (proteolysis targeting chimeric molecule). This Protac consisted of an SCF(beta-TRCP)-binding phosphopeptide derived from IkappaBalpha linked to ovalicin, which covalently binds MetAP-2. In this study, we employed this approach to target two different proteins, the estrogen (ER) and androgen (AR) receptors, which have been implicated in the progression of breast and prostate cancer, respectively. We show here that an estradiol-based Protac can enforce the ubiquitination and degradation of the alpha isoform of ER in vitro, and a dihydroxytestosterone-based Protac introduced into cells promotes the rapid disappearance of AR in a proteasome-dependent manner. Future improvements to this technology may yield a general approach to treat a number of human diseases, including cancer.
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A phosphopeptide linked to oestradiol recruits oestrogen receptor (ER) to BTRC, leading to ER ubiquitylation and degradation.
“a phosphopeptide linked to oestradiol recruits oestrogen receptor (ER) to BTRC, leading to ER ubiquitylation and degradation 113 .”
From Targeted protein degradation: expanding the toolbox (2019) · cites this paper as [113]
Phosphodegron motifs bind the central cavity of the BTRC WDR domain.
“Phosphodegron motifs (yellow) bind the central cavity of the BTRC WDR domain”
From Targeted protein degradation: expanding the toolbox (2019) · cites this paper as [113]
BTRC was efficiently recruited by PROTACs composed of a BTRC-interacting peptide and small-molecule ligands for METAP2, oestrogen receptors, or androgen receptors, leading to degradation of their targets.
“BTRC was efficiently recruited by PROTACs composed of a BTRC-interacting peptide and small-molecule ligands for METAP2, the oestrogen or androgen receptors, leading to degradation of their respective targets 2,113 .”
From Targeted protein degradation: expanding the toolbox (2019) · cites this paper as [113]
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- Authors
- Sakamoto, K. M., Kim, K. B., Verma, R., Ransick, A., Stein, B., Crews, C. M., & Deshaies, R. J.
- Affiliations
- California Institute of Technology (US)
- University of Kentucky (US)
- Celgene (United States) (US)
- Yale University (US)
- Corresponding author
- Sakamoto, Kathleen M.
- Deshaies, Raymond J.
- Venue
- Molecular & Cellular Proteomics
- Publisher
- Elsevier BV
- Published
- 2003-12
- Volume
- 2
- Issue
- 12
- Pages
- 1350-1358
- ISSN
- 1535-9476 (ISSN-L)
- OpenAlex
- W2131441324
- Cited by
- 425
- References
- 25
- Citations by year
- 2026: 30 · 2025: 33 · 2024: 47 · 2023: 32 · 2022: 51 · 2021: 39 · 2020: 40 · 2019: 25 · 2018: 18 · 2017: 21 · 2016: 9 · 2015: 6 · 2014: 5 · 2013: 5 · 2012: 5
- FWCI
- 2.86
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Molecular & Cellular Proteomics (publishedVersion, cc-by)
- PubMed (publishedVersion)
- CaltechAUTHORS (California Institute of Technology) (submittedVersion)
- Funders
- U.S. Department of Defense
- Susan G. Komen for the Cure
- Celgene
- California Institute of Technology
- National Cancer Institute (P50CA092131)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Prostate Cancer Treatment and Research
- Keywords
- PROTACs, ubiquitination, protein degradation, SCF ubiquitin ligase, estrogen receptor alpha, androgen receptor, estradiol, dihydrotestosterone, breast cancer, prostate cancer, small molecule inhibitors, proteasome
- MeSH terms
- NF-KappaB Inhibitor alpha, Breast Neoplasms, Cell Line, Cloning, Molecular, Estradiol, Feasibility Studies, Female, Humans, Hydroxytestosterones, Male, Phosphopeptides, Prostatic Neoplasms, Protein Binding, Receptors, Androgen, Ubiquitins, I-kappa B Proteins, SKP Cullin F-Box Protein Ligases, Proteasome Endopeptidase Complex, Estrogen Receptor alpha
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