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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Book ChapterDOI
Targeted Protein Degradation
Nello Mainolfi,Tim Rasmusson +1 more
TL;DR: This chapter reviews the field especially focusing on heterobifunctional molecule-driven target degradation and highlights great progress but also gaps needed to be filled as the field moves toward clinical validation.
Journal ArticleDOI
Recent advances in epigenetic proteolysis targeting chimeras (Epi-PROTACs).
TL;DR: This review will present the most relevant progresses made, especially in the last two years, in the application of PROTACs technology to the three main classes of e-POIs: "writers", "erasers" and "readers".
Journal ArticleDOI
Beyond Proteolysis-Targeting Chimeric Molecules: Designing Heterobifunctional Molecules Based on Functional Effectors.
TL;DR: Heterobifunctional molecules other than PROTACs are introduced, the limitations of existing molecules are summarized, the main challenges are listed, and perspectives for future research directions are proposed, providing insight into alternative design strategies based on substrate-proximity-based targeting.
Journal ArticleDOI
Ligand-regulated peptide aptamers that inhibit the 5'-AMP-activated protein kinase
TL;DR: 15 LiRP proteins, some of which serve as poor substrates of AMPK, inhibit the kinase as pseudosubstrates in a Rapamycin-regulated fashion in vitro, an effect that is largely competitive with substrate peptide and mediated by an increase in the Kinase's apparent K(m) for substrate peptides.
Journal ArticleDOI
Development of tau-directed small molecule modulators for Alzheimer's disease: a recent patent review (2014-2018).
Ha E Lee,Ha E Lee,Dami Lim,Dami Lim,Jae Y Lee,Sang Min Lim,Sang Min Lim,Ae N Pae,Ae N Pae,Ae N Pae +9 more
TL;DR: In this review, a variety of t Tau-directed strategies to rescue tau-mediated neurotoxicity will be reviewed especially focusing on small molecules, and recent patents published from 2014 to 2018 that integrate efforts to develop tau -directed small molecules for the treatment of AD are reviewed.
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