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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Opportunities and Challenges of Small Molecule Induced Targeted Protein Degradation
Ming He,Wenxing Lv,Yu Rao +2 more
TL;DR: Proteolysis targeting chimeras (PROTAC) represents a new type of small molecule induced protein degradation technology that has emerged in recent years as mentioned in this paper, which uses bifunctional small molecules to induce ubiquitination of target proteins and utilizes intracellular proteasomes for chemical knockdown.
Journal ArticleDOI
Discovery of small molecule ligands for the von Hippel-Lindau (VHL) E3 ligase and their use as inhibitors and PROTAC degraders
Claudia J. Diehl,Alessio Ciulli +1 more
TL;DR: The structure-based design of VHL ligands, their application as inhibitors in their own right, and their implementation into rationally designed, potent PROTAC degraders of various target proteins are covered.
Journal ArticleDOI
Emerging protein degradation strategies: expanding the scope to extracellular and membrane proteins.
Jiayi Lin,Jinmei Jin,Yi-Wen Shen,Li-Jun Zhang,Gang Gong,Huiting Bian,Hong-Zhuan Chen,Dale G. Nagle,Ye Wu,Weidong Zhang,Weidong Zhang,Xin Luan +11 more
Abstract: Classic small molecule inhibitors that directly target pathogenic proteins typically rely on the accessible binding sites to achieve prolonged occupancy and influence protein functions. The emerging targeted protein degradation (TPD) strategies exemplified by PROteolysis TArgeting Chimeras (PROTACs) are revolutionizing conventional drug discovery modality to target proteins of interest (POIs) that were categorized as "undruggable" before, however, these strategies are limited within intracellular POIs. The novel new degrader technologies such as LYsosome-TArgeting Chimaeras (LYTACs) and Antibody-based PROTACs (AbTACs) have been successfully developed to expand the scope of TPD to extracellular and membrane proteins, fulfilling huge unmet medical needs. Here, we systematically review the currently viable protein degradation strategies, emphasize that LYTACs and AbTACs turn a new avenue for the development of TPD, and highlight the potential challenges and directions in this vibrant field.
Journal ArticleDOI
Protein degraders enter the clinic — a new approach to cancer therapy
Journal ArticleDOI
Direct-to-Biology Accelerates PROTAC Synthesis and the Evaluation of Linker Effects on Permeability and Degradation
Charles E. Hendrick,Jeff R. Jorgensen,Charu Chaudhry,Iulia I. Strambeanu,Jean-François Brazeau,Jamie M. Schiffer,Zhicai Shi,Jennifer D. Venable,Scott E. Wolkenberg +8 more
TL;DR: Unexpected aspects of linker SAR was discovered, consistent with literature reports on “linkerology”, and the method dramatically speeds up empirical optimization, which has the potential to rapidly expand training sets for more complex prediction models.
References
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Journal ArticleDOI
Phosphorylation meets ubiquitination: the control of NF-[kappa]B activity.
Michael Karin,Yinon Ben-Neriah +1 more
TL;DR: Recent progress has been made in understanding the details of the signaling pathways that regulate NF-kappaB activity, particularly those responding to the proinflammatory cytokines tumor necrosis factor-alpha and interleukin-1.
Journal ArticleDOI
IKK-1 and IKK-2: Cytokine-Activated IκB Kinases Essential for NF-κB Activation
Frank Mercurio,Hengyi Zhu,Brion W. Murray,Andrej Shevchenko,Brydon L. Bennett,Jian Wu Li,David B. Young,Miguel Barbosa,Matthias Mann,Anthony M. Manning,Anjana Rao +10 more
TL;DR: In this article, a large multiprotein complex, the IkappaB kinase (IKK) signalsome, was purified from HeLa cells and found to contain a cytokine-inducible IKK kinase activity that phosphorylates IappaB-alpha and IKK-beta.
Journal ArticleDOI
SCF and Cullin/RING H2-Based Ubiquitin Ligases
TL;DR: This review is focused on a conserved ubiquitin ligase complex known as SCF that plays a key role in marking a variety of regulatory proteins for destruction by the 26S proteasome.
Journal ArticleDOI
Transduction of full-length TAT fusion proteins into mammalian cells:TAT-p27Kip1 induces cell migration
Hikaru Nagahara,Adamina Vocero-Akbani,Eric L. Snyder,Alan L. Ho,Dawn G. Latham,Natalie A. Lissy,Michelle Becker-Hapak,Sergei A. Ezhevsky,Steven F. Dowdy +8 more
TL;DR: Transduction of full-length TAT fusion proteins into mammalian cells: TAT-p27 Kip1 induces cell migration and promotes cell migration in mice.
Journal ArticleDOI
Epoxomicin, a potent and selective proteasome inhibitor, exhibits in vivo antiinflammatory activity
TL;DR: In this article, the authors used biotinylated-epoxomicin as a molecular probe and showed that it covalently binds to the LMP7, X, MECL1, and Z catalytic subunits of the proteasome.
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