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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Targeted protein degradation: A promise for undruggable proteins
TL;DR: Targeted Protein Degradation (TPD) strategies have also been explored to target previously undruggable proteins, such as transcription factors as discussed by the authors, which is a potential therapeutic modality.
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Heterobifunctional Molecules Induce Dephosphorylation of Kinases-A Proof of Concept Study.
Sayumi Yamazoe,Jeffrey Tom,Yue Fu,Wenqiong Wu,Liang Zeng,Changlei Sun,Qi Liu,Jie Lin,Kui Lin,Wayne J. Fairbrother,Steven T. Staben +10 more
TL;DR: This work represents the first examples of small molecules recruiting non-native partners to induce removal of a PTM, phosphorylation, which was designed to promote the proximity of a protein phosphatase to protein targets.
Journal ArticleDOI
Discovery of SIAIS178 as an Effective BCR-ABL Degrader by Recruiting Von Hippel-Lindau (VHL) E3 Ubiquitin Ligase.
Quanju Zhao,Ren Chaowei,Linyi Liu,Chen Jinju,Yubao Shao,Ning Sun,Renhong Sun,Kong Ying,Xinyu Ding,Xianfang Zhang,Youwei Xu,Bei Yang,Yin Qianqian,Xiaobao Yang,Biao Jiang +14 more
TL;DR: The design, synthesis, and evaluation of novel proteolysis-targeting chimeric (PROTAC) small molecules targeting BCR-ABL which connect dasatinib and VHL E3 ubiquitin ligase ligand by extensive optimization of linkers yield SIAIS178, which achieves significant growth inhibition of BCR -ABL+ leukemic cells in vitro and induces substantial tumor regression against K562 xenograft tumors in vivo.
Journal ArticleDOI
Enzymatic Logic of Ubiquitin Chain Assembly.
TL;DR: This review discusses the evidence in support of the alternative models of transferring one ubiquitin at a time to a growing substrate-linked chain, and outlines emerging principles of chain assembly: multisite interactions, distinct mechanisms of chain initiation and elongation, optimal positioning of ubiquitins that are ultimately conjugated to each other, and substrate-assisted catalysis.
Journal ArticleDOI
RNA‑PROTACs: Degraders of RNA‑Binding Proteins
TL;DR: The RNA‐PROTAC approach opens the way to rapid, selective targeting of RBPs in a rational and general fashion.
References
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