Protacs: Chimeric molecules that target proteins to the Skp1–Cullin–F box complex for ubiquitination and degradation
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The intracellular levels of many proteins are regulated by ubiquitin-dependent proteolysis. One of the best-characterized enzymes that catalyzes the attachment of ubiquitin to proteins is a ubiquitin ligase complex, Skp1-Cullin-F box complex containing Hrt1 (SCF). We sought to artificially target a protein to the SCF complex for ubiquitination and degradation. To this end, we tested methionine aminopeptidase-2 (MetAP-2), which covalently binds the angiogenesis inhibitor ovalicin. A chimeric compound, protein-targeting chimeric molecule 1 (Protac-1), was synthesized to recruit MetAP-2 to SCF. One domain of Protac-1 contains the IκBα phosphopeptide that is recognized by the F-box protein β-TRCP, whereas the other domain is composed of ovalicin. We show that MetAP-2 can be tethered to SCF β -TRCP , ubiquitinated, and degraded in a Protac-1-dependent manner. In the future, this approach may be useful for conditional inactivation of proteins, and for targeting disease-causing proteins for destruction.
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Proteolysis-targeting chimeras (PROTACs) are bifunctional molecules designed to simultaneously engage a protein of interest and the cell's ubiquitination machinery, facilitating the ubiquitination of the target protein.
“Proteolysis-targeting chimeras (PROTACs) are bifunctional molecules designed to simultaneously engage a protein of interest and the cell’s ubiquitination machinery, facilitating the ubiquitination of the target protein [73,74].”
From KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance (2024) · cites this paper as [74]
Bivalent degraders such as PROTACs operate through the principle of induced proximity.
“Bivalent degraders, such as proteolysis-targeting chimeras (PROtAcs) operate through the principle of induced proximity (Sakamoto et al. 2001;Deshaies 2015).”
From From serendipity to strategy: molecular glue degraders in cancer therapeutics (2025) · cites this paper as Sakamoto et al. 2001
The concept of targeted protein degradation was first introduced by Crews, Deshaies and colleagues in 2001.
“the concept of targeted protein degradation was first introduced by crews, Deshaies and colleagues in 2001 (Sakamoto et al. 2001).”
From From serendipity to strategy: molecular glue degraders in cancer therapeutics (2025) · cites this paper as Sakamoto et al. 2001
Within this complex, the target protein is tagged with ubiquitin, facilitating its recognition and subsequent degradation by the proteasome.
“Within this complex, the target protein is tagged with ubiquitin, facilitating its recognition and subsequent degradation by the proteasome.480,481”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [481]
As a heterobifunctional molecule, PROTAC simultaneously targets the protein of interest and the E3 ubiquitin ligase, forming a ternary complex.
“As a heterobifunctional molecule, PROTAC simultaneously targets the protein of interest and the E3 ubiquitin ligase, forming a ternary complex.”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [481]
At the core of PROTAC's mechanism of action lies the degradation of target proteins via the ubiquitin-proteasome system (UPS).
“At the core of PROTAC’s mechanism of action lies the degradation of target proteins via the ubiquitin-proteasome system (UPS).”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [481]
TPD uses small molecules (degraders) to hijack the cellular degradation machinery by recruiting E3 ubiquitin ligases to proteins of interest, which would not otherwise be recognized as substrates.
“TPD uses small molecules (degraders) to hijack the cellular degradation machinery by recruiting E3 ubiquitin ligases to proteins of interest (POI), which would not otherwise be recognized as substrates (Sakamoto et al., 2001)”
From Mapping the Degradable Kinome Provides a Resource for Expedited Degrader Development (2020) · cites this paper as Sakamoto et al., 2001
PROTACs induce target protein degradation by drawing the target protein into a ternary complex with an E3 ligase.
“If these two groups are connected via a carefully-chosen chemical linker, the resulting compound can induce formation of a ternary complex that includes the target protein, the PROTAC, and the E3 ligase. The resulting proximity between target protein and E3 ligase can then lead to ubiquitination of the target protein, and ultimately its degradation 1.”
From Rationalizing PROTAC-Mediated Ternary Complex Formation Using Rosetta (2021) · cites this paper as [1]
Protac-1 acted as a tether between METAP2 and β-TRCP, enabling the ligase to ubiquitylate METAP2 in extracts from unfertilized Xenopus laevis eggs.
“Protac-1 acted as a tether between METAP2 and β-TRCP, enabling the ligase to ubiquitylate METAP2 in extracts from unfertilized Xenopus laevis eggs.”
From PROTAC targeted protein degraders: the past is prologue (2022) · cites this paper as [9]
In vitro proof of concept for the first fully synthetic PROTAC, dubbed Protac-1, was reported in 2001.
“In vitro proof of concept for the first fully synthetic PROTAC, dubbed Protac-1, was reported in 2001 (ref.9).”
From PROTAC targeted protein degraders: the past is prologue (2022) · cites this paper as [9]
The concept of E3 ligases with unique expression profiles to enable tissue- and cell-type-specific target degradation was originally proposed in the landmark PROTAC paper by Sakamoto et al. 20 years ago.
“a concept originally proposed in the landmark PROTAC paper by Sakamoto et al.9 20 years ago.”
From PROTAC targeted protein degraders: the past is prologue (2022) · cites this paper as [9]
The first PROTAC described consisted of an ovalicin headgroup that bound methionine-aminopeptidase 2 (MetAP-2) linked to an IκBα derived peptide headgroup that bound the Skp1-cullin-F-Box (SCF) complex.
“The first PROTAC described consisted of an ovalicin headgroup that bound methionine-aminopeptidase 2 (MetAP-2) linked to an IκBα derived peptide headgroup that bound the Skp1–cullin–F-Box (SCF) complex [62].”
From Advances in targeted degradation of endogenous proteins (2019) · cites this paper as [62]
The first PROTAC efficiently degraded MetAP-2 in Xenopus oocyte extracts, but it was not cell permeable.
“This molecule efficiently degraded MetAP-2 in Xenopus oocyte extracts, however it was not cell permeable [62].”
From Advances in targeted degradation of endogenous proteins (2019) · cites this paper as [62]
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 [2]
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- Authors
- Sakamoto, K. M., Kim, K. B., Kumagai, A., Mercurio, F., Crews, C. M., & Deshaies, R. J.
- Affiliations
- California Institute of Technology (US)
- Corresponding author
- Deshaies, Raymond J.
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2001-07-03
- Volume
- 98
- Issue
- 15
- Pages
- 8554-8559
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC37474
- OpenAlex
- W2151683271
- Cited by
- 2,609
- References
- 25
- Citations by year
- 2026: 355 · 2025: 435 · 2024: 399 · 2023: 309 · 2022: 278 · 2021: 224 · 2020: 193 · 2019: 118 · 2018: 75 · 2017: 48 · 2016: 28 · 2015: 15 · 2014: 13 · 2013: 9 · 2012: 10
- FWCI
- 2.79
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- CaltechAUTHORS (California Institute of Technology) (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- Leukemia and Lymphoma Society
- University of California, Los Angeles
- Jonsson Comprehensive Cancer Center
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chemical Synthesis and Analysis
- Keywords
- PROTACs, chimeric molecules, SCF ubiquitin ligase, β-TrCP, ubiquitination, protein degradation, targeted protein degradation
- MeSH terms
- NF-KappaB Inhibitor alpha, Aminopeptidases, Animals, Cell Extracts, Cell Line, Transformed, DNA-Binding Proteins, Humans, Metalloendopeptidases, Ovum, Peptide Synthases, Protein Binding, Recombinant Fusion Proteins, Ubiquitins, Xenopus laevis, I-kappa B Proteins, SKP Cullin F-Box Protein Ligases
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