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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A PROTAC peptide induces durable β-catenin degradation and suppresses Wnt-dependent intestinal cancer.
Hongwei Liao,Xiang Li,Lianzheng Zhao,Yalong Wang,Xiaodan Wang,Ye Wu,Xin Zhou,Wei Fu,Lei Liu,Honggang Hu,Honggang Hu,Ye-Guang Chen +11 more
TL;DR: The findings suggest that xStAx-VHLL exhibits the ability of cancer prevention and cure, highlighting the potential of β-catenin degrader PROTACs as a new class of promising anticancer agent.
Journal ArticleDOI
Exploring the functional complexity of cellular proteins by protein knockout.
TL;DR: It is shown that the engineered Skp1, Cullin 1, and F-box-containing βTrCP substrate receptor ubiquitin-proteolytic system, designated protein knockout, could achieve not only total elimination but also rapid and systematic reduction of a given cellular protein.
Journal ArticleDOI
BET Bromodomain as a Target of Epigenetic Therapy.
TL;DR: Recent progress in epigenetic therapy targeting the BET bromodomain is reviewed, with a focus on BET proteins, which have attracted interest as candidate therapeutic targets due to their putative involvement in the pathogenesis of various diseases, including cancer and inflammatory diseases.
Journal ArticleDOI
Snapshots and ensembles of BTK and cIAP1 protein degrader ternary complexes
James Schiemer,Reto Horst,Yilin Meng,Justin I. Montgomery,Yingrong Xu,Xidong Feng,Kris A. Borzilleri,Daniel P. Uccello,Carolyn A. Leverett,Stephen P. Brown,Ye Che,Matthew Frank Brown,Matthew Merrill Hayward,Adam M. Gilbert,Mark C. Noe,Matthew F. Calabrese +15 more
TL;DR: This work uses a combination of biochemical, biophysical and structural studies to characterize degrader-mediated ternary complexes of Bruton’s tyrosine kinase and cIAP1 and shows that cooperativity is not always correlated with degradation efficiency.
Journal ArticleDOI
Targeting Nuclear Receptors with PROTAC degraders.
TL;DR: How PROTAC degraders afford a novel approach to abrogate the downstream signaling activity of NRs is discussed, and six broad functional reasons why PROTACDegraders are preferable to the classical ligand binding pocket antagonists are highlighted.
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