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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Discovery of CRBN as a target of thalidomide: a breakthrough for progress in the development of protein degraders.
TL;DR: This discovery was a breakthrough in the current rapid development of protein-degrading agents because clarification of the mechanism of action of thalidomide derivatives has demonstrated the clinical value of these compounds.
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Targeted Protein Internalization and Degradation by ENDosome TArgeting Chimeras (ENDTACs)
Dhanusha A. Nalawansha,Stacey-Lynn Paiva,Diane N Rafizadeh,Mariell Pettersson,Liena Qin,Craig M. Crews +5 more
TL;DR: A proof-of-concept study suggests that using ENDTACs to co-opt the endosomal–lysosomal degradation pathway, in contrast to PROTACs using the UPS, may provide an avenue for degrading extracellular targets such as cytokines.
Journal ArticleDOI
PROTACs suppression of GSK-3β, a crucial kinase in neurodegenerative diseases.
TL;DR: Western-blot data showed compound PG21 can effectively degrade GSK-3β in a dose-dependent manner, which can induce 44.2% protein degradation at 2.8 μM, and pharmacological experiments revealed that the ability of PG21 to degrade GK3β is mediated by the ubiquitin-proteasome system (UPS).
Journal ArticleDOI
Targeting Protein Kinases Degradation by PROTACs.
TL;DR: A detailed summary of the most recent signs of progress in PROTACs targeting different kinases, primarily focusing on new chemical entities in medicinal chemistry, can be found in this paper, where the E3 ligase for degrading the whole target protein via the ubiquitin-proteasome pathway.
Journal ArticleDOI
BCR-ABL1 Tyrosine Kinase Complex Signaling Transduction: Challenges to Overcome Resistance in Chronic Myeloid Leukemia
Gustavo P. Amarante-Mendes,Aamir Rana,Tarcila Santos Datoguia,Nelson Hamerschlak,Gabriela Brumatti +4 more
TL;DR: Although B CR-ABL1 tyrosine kinase is necessary to initiate and establish the malignant phenotype of Ph-related leukemia, in the later advanced phase of the disease, BCR-ABl1-independent mechanisms are also in place and the major challenges regarding immunologic/pharmacologic combined therapies are discussed.
References
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