Protacs: chimeric molecules that target proteins to the Skp1-Cullin-F box complex for ubiquitination and degradation.
Kathleen M. Sakamoto,Kyung Bo Kim,Akiko Kumagai,Frank Mercurio,Craig M. Crews,Raymond J. Deshaies +5 more
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TLDR
It is shown that MetAP-2 can be tethered to SCFβ-TRCP, ubiquitinated, and degraded in a Protac-1-dependent manner, which may be useful for conditional inactivation of proteins, and for targeting disease-causing proteins for destruction.Abstract:
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 SCFβ-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.read more
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Targeting SHP2 as a therapeutic strategy for inflammatory diseases.
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Hijacking Methyl Reader Proteins for Nuclear-Specific Protein Degradation.
TL;DR: A novel approach to induce protein degradation by hijacking a methyl reader:E3 ligase complex by co-opting this natural mechanism is reported and envisioned as a generalizable approach to utilize other reader protein-associated E 3 ligase complexes in PROTAC design to expand the E3 ligases toolbox and explore the full potential of TPD.
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Targeted Protein Degradation in Antibacterial Drug Discovery
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A modular PROTAC design for target destruction using a degradation signal based on a single amino acid
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Targeted BRD4 protein degradation by dBET1 ameliorates acute ischemic brain injury and improves functional outcomes associated with reduced neuroinflammation and oxidative stress and preservation of blood–brain barrier integrity
Lei Liu,Changjun Yang,Bianca P. Lavayen,Ryland J. Tishko,Jonathan R. LaRochelle,Eduardo Candelario-Jalil +5 more
TL;DR: In this article , the authors showed that dBET1 significantly reduced inflammation and oxidative stress after stroke, indicated by multiple pro-inflammatory cytokines and chemokines, including IL-1β, IL-6, TNF-α, CCL2, CXCL1 and CCL10.
References
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