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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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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Design, synthesis, and biological evaluation of Wee1 kinase degraders.
Shulei Zhu,Jie Liu,Donghuai Xiao,Peipei Wang,Jingkun Ma,Xiaobei Hu,Jingfeng Fu,Yubo Zhou,Jia Li,Wei Lu +9 more
TL;DR: In this article , a series of Wee1 degraders were designed and synthesized based on PROTAC technology by linking AZD1775 with CRBN ligands through linkers of different lengths and types.
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Protein Polymerization as a Novel Targeted Protein Degradation Mechanism.
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Extracellular protein homeostasis in neurodegenerative diseases
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PROTAC: targeted drug strategy. Principles and limitations
O. Koroleva,Yulia V. Dutikova,A. V. Trubnikov,F. A. Zenov,E. V. Manasova,Alexander A. Shtil,Alexander V. Kurkin +6 more
TL;DR: The PROTAC (Proteolysis TArgeting Chimera) technology is a method of targeting intracellular proteins previously considered undruggable as mentioned in this paper , which utilizes the ubiquitin-proteasome system in cells to specifically degrade target proteins, thereby offering significant advantages over conventional smallmolecule inhibitors of the enzymatic function.
References
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