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
Citations
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Journal ArticleDOI
Design, Synthesis and In Vitro Investigation of Cabozantinib-Based PROTACs to Target c-Met Kinase
A. A. Sachkova,Daria V. Andreeva,Alexander S. Tikhomirov,Alexander M. Scherbakov,D.I. Salnikova,Danila V. Sorokin,Fedor B Bogdanov,Yulia D. Rysina,Andrey E. Shchekotikhin,Ekaterina S. Shchegravina,Alexey Yu. Fedorov +10 more
TL;DR: In this paper , a series of c-Met-targeting cabozantinib-based PROTACs were developed, bearing a VHL-ligand as an E3-ligase binding moiety and glycol-based linkers.
Patent
Diagnosis and treatment of infectious diseases through indel-differentiated proteins
TL;DR: A compound capable of specifically binding to pathogen EF-1α but not host EF 1α is defined in this article, where the compound binds to any part of an amino acid sequence having at least 70% sequence identity to amino acids 240-230 of SEQ ID NO:22.
Journal ArticleDOI
Computational strategies for PROTAC drug discovery
TL;DR: In this article , the authors summarize recent efforts in the application of molecular docking and virtual screening for PROTAC drug discovery, and discuss the potential challenges of such methods in drug discovery.
Dissertation
Identification of new regulators for PML nuclear bodies
TL;DR: This thesis project was to identify new regulators of PML Nuclear Bodies, and by extension of the SUMO pathway, using PML-NBs, which are extremely sensitive to global cellular SUMOylation level, as a read out, and identified FBXO9 as the F-Box capable of specifically recognizing PML, causing its ubiquitination by SCFFBxO9 complex and subsequent degradation by the proteasome.
References
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Journal ArticleDOI
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