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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Utilizing PROTAC technology to address the on-target platelet toxicity associated with inhibition of BCL-XL
TL;DR: The development of a PROTAC BCL-XL degrader, XZ424, is reported, which has increased selectivity for Bcl-XL-dependent MOLT-4 cells over human platelets compared with conventional B CL-XL inhibitors.
Journal ArticleDOI
A nano-predator of pathological MDMX construct by clearable supramolecular gold(I)-thiol-peptide complexes achieves safe and potent anti-tumor activity.
Siqi Yan,Jin Yan,Dan Liu,Xiang Li,Qianyan Kang,Weiming You,Jinghua Zhang,Lei Wang,Zhiqi Tian,Wuyuan Lu,Wenjia Liu,Wangxiao He +11 more
TL;DR: In this paper, a peptide-based molecular glue (MG) was designed to target a tumor-driving protein, MDMX, for degradation, and nanoengineered it into a supramolecular gold(I)-thiol-peptide complex (Nano-MP) to implement the proteolysis recalcitrance, cellular internalization, and glutathione-triggered release.
Journal ArticleDOI
Unraveling the Role of Linker Design in Proteolysis Targeting Chimeras.
TL;DR: In this article, a multidisciplinary approach to alleviate the bottleneck in the development of proteolysis targeting chimeras (PROTACs) is described, and a model generated from a curated list of linker SARs studies normalized to reflect how linear linker length affects the observed degradation potency is presented.
Journal ArticleDOI
Regulation of target protein knockdown and labeling using ligand-directed Ru(bpy)3 photocatalyst.
TL;DR: This mechanistic study suggests that TRT scavenges (1)O2, concomitant with the coupling reaction to the tyrosyl radical generated by Ru( bpy)3, can be regulated by the Ru(bpy) 3 photocatalysts in the absence or presence of TRT.
Patent
Compounds and methods for the targeted degradation of bromodomain-containing proteins
TL;DR: In this paper, a broad range of pharmacological activities associated with compounds according to the present invention, consistent with the degradation/inhibition of targeted polypeptides, are described.
References
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