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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Genome-Wide Estrogen Receptor Activity in Breast Cancer.
Anca M. Farcas,Anca M. Farcas,Sankari Nagarajan,Sankari Nagarajan,Sabina Cosulich,Jason S. Carroll +5 more
TL;DR: A dynamic interplay between some of these factors which co-occupy ER-bound regulatory elements, their contribution to estrogen signaling, and their possible therapeutic applications is focused on.
Journal ArticleDOI
Phenyl-Glutarimides: Alternative Cereblon Binders for the Design of PROTACs.
Jaeki Min,Anand Mayasundari,Fatemeh Keramatnia,Barbara Jonchere,Seung Wook Yang,Jamie Jarusiewicz,Marisa Actis,Sourav Das,Brandon Young,Jake Slavish,Lei Yang,Yong Li,Xiang Fu,Shalandus H. Garrett,Mi-Kyung Yun,Zhenmei Li,Stanley Nithianantham,Sergio C. Chai,Taosheng Chen,Anang A. Shelat,Richard E. Lee,Gisele Nishiguchi,Stephen W. White,Martine F. Roussel,Patrick Ryan Potts,Marcus Fischer,Zoran Rankovic +26 more
TL;DR: In this paper, phenyl glutarimide (PG) analogues of CRBN have been used to design PROTACs with high affinity for CRBN with high ligand efficiency and displayed improved chemical stability.
Patent
Tank-binding kinase-1 protacs and associated methods of use
TL;DR: In this paper, a bifunctional compound with E3 ubiquitin ligase binding moiety was proposed to degrade and inhibit TBK 1. The present invention exhibits a broad range of pharmacological activities associated with compounds according to the present invention, consistent with the degradation/inhibition of TBK1.
Journal ArticleDOI
Insulin signaling regulates longevity through protein phosphorylation in Caenorhabditis elegans
Wen-Jun Li,Chen Wei Wang,Chen Wei Wang,Li Tao,Yong Hong Yan,Mei Jun Zhang,Zexian Liu,Zexian Liu,Yu-Xin Li,Han Qing Zhao,Xue Mei Li,Xian Dong He,Yu Xue,Yu Xue,Meng-Qiu Dong +14 more
TL;DR: This study profiles IIS-dependent phosphorylation changes in a large-scale quantitative phosphoproteomic analysis of wild-type and three IIS mutant Caenorhabditis elegans strains and reveals detailed functional insights into longevity.
Journal ArticleDOI
The state of the art of PROTAC technologies for drug discovery.
TL;DR: Protein degradation technology has progressed dramatically since 2001 when proteolysis targeting chimera (PROTAC) was first reported as mentioned in this paper , which greatly broaden the spectrum of targets and the scope of clinical applications for the treatment of cancer, neurodegenerative diseases and virus diseases.
References
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