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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Journal ArticleDOI
Discovery of a Potent and Selective Degrader for USP7.
Y. Pei,Jingfeng Fu,Yunkai Shi,Meng-Meng Zhang,Guanghao Luo,Xiaomin Luo,Ning Song,Tian Mi,Yaxi Yang,Jia Li,Yubo Zhou,Bing-Bing Zhou +11 more
TL;DR: U7D-1 showed selective and effective USP7 degradation, and maintained potent cell growth inhibition in p53 mutant cancer cells, with USp7 inhibitor showing no activity, which clearly demonstrated the practicality and importance of PROTAC as a preliminary chemical tool for investigating USP 7 protein functions and a promising method for potential p53 Mutant cancer therapy.
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Avoid the trap: Targeting PARP1 beyond human malignancy
Chiho Kim,Chuo Chen,Yonghao Yu +2 more
TL;DR: In this paper, the authors provide an overview of the basic biology of PARP1 trapping and its implications in disease, and discuss the recent development of PROTAC compounds, and their utility as "non-trapping"PARP1 degraders for the potential amelioration of non-oncological diseases driven by aberrant PARP 1 activation.
Journal ArticleDOI
Discovery of a potent and selective proteolysis targeting chimera (PROTAC) degrader of NSD3 histone methyltransferase.
Yaoliang Sun,Yuqing Zhang,Xiaoai Chen,Aisong Yu,Wenhao Du,Yuting Huang,F-R Wu,Lei Yu,Jiayi Li,Cuiyun Wen,Hong Yang,Qiongyu Shi,Meiyu Geng,Xun Huang,Shilin Xu +14 more
TL;DR: In this paper , a series of small-molecule NSD3 degraders based on the proteolysis targeting chimera (PROTAC) strategy was proposed.
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Proteome-scale induced proximity screens reveal highly potent protein degraders and stabilizers
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TL;DR: This study used a proteome-scale platform to identify hundreds of human proteins that can promote the degradation or stabilization of a target protein in a proximity-dependent manner and identified the top degraders, which were more potent against multiple therapeutically relevant targets than the currently used E3s CBRN and VHL.
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