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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Book ChapterDOI
Targeting Cullin-RING Ubiquitin Ligases and the Applications in PROTACs.
TL;DR: This chapter systematically review the development of small molecules that target CRLs and especially emphasize the applications of C RLs in a chemical chimera for protein degradation, termed proteolysis-targeting chimeras (PROTACs).
Journal ArticleDOI
PDTAC: Targeted Photodegradation of GPX4 Triggers Ferroptosis and Potent Antitumor Immunity.
TL;DR: The targeted photolysis of GPX4 resulted in dominant ferroptotic cell death in malignant cancer cells and exhibited potent immunogenicity in vitro and efficiently elicited antitumor immunity in vivo.
Journal ArticleDOI
Homobivalent, Trivalent, and Covalent PROTACs: Emerging Strategies for Protein Degradation.
TL;DR: This work will summarize the latest development of representative PROTACs focusing on research mainly in past 10 years and discuss their advantages and disadvantages, as well as the outlook and perspectives on the associated challenges and future directions.
Posted ContentDOI
Prioritisation of oncology therapeutic targets using CRISPR-Cas9 screening
Fiona M. Behan,Francesco Iorio,Francesco Iorio,Emanuel Gonçalves,Gabriele Picco,Charlotte M. Beaver,Rita Santos,Yanhua Rao,Rizwan Ansari,Sarah Harper,David A. Jackson,Rebecca McRae,Rachel Pooley,Piers Wilkinson,David J. Dow,Carolyn Buser-Doepner,Euan A. Stronach,Julio Saez-Rodriguez,Kosuke Yusa,Mathew J. Garnett +19 more
TL;DR: Per genome-scale CRISPR-Cas9 screens in 204 human cancer cell lines from 12 cancer-types are performed and a data-driven framework to prioritise cancer therapeutic candidates is developed and one of the most promising dependencies, Werner syndrome RecQ helicase, is taken and verified as a candidate target for tumours with microsatellite instability.
Journal ArticleDOI
Targeted protein degradation: the new frontier of antimicrobial discovery?
TL;DR: Targeted protein degradation aims to hijack endogenous protein quality control systems to achieve direct knockdown of protein targets as mentioned in this paper, a technique that utilizes event-based pharmacology to produce therapeutic outcomes, a feature that distinguishes it from classical occupancy-based inhibitors.
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