Development of Protacs to Target Cancer-promoting Proteins for Ubiquitination and Degradation
Kathleen M. Sakamoto,Kathleen M. Sakamoto,Kyung Bo Kim,Rati Verma,Andy Ransick,Bernd Stein,Craig M. Crews,Raymond J. Deshaies +7 more
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It is shown that an estradiol- based Protac can enforce the ubiquitination and degradation of the α isoform of ER in vitro, and a dihydroxytestosterone-based Protac introduced into cells promotes the rapid disappearance of AR in a proteasome-dependent manner.About:
This article is published in Molecular & Cellular Proteomics.The article was published on 2003-12-01 and is currently open access. It has received 319 citations till now. The article focuses on the topics: Proteolysis targeting chimera & Ubiquitin ligase complex.read more
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Induced protein degradation: an emerging drug discovery paradigm
Ashton C. Lai,Craig M. Crews +1 more
TL;DR: Induced protein degradation has the potential to reduce systemic drug exposure, the ability to counteract increased target protein expression that often accompanies inhibition of protein function and the potential ability to target proteins that are not currently therapeutically tractable, such as transcription factors, scaffolding and regulatory proteins.
Journal ArticleDOI
Hijacking the E3 Ubiquitin Ligase Cereblon to Efficiently Target BRD4
Jing Lu,Yimin Qian,Martha Altieri,Hanqing Dong,Jing Wang,Kanak Raina,John Hines,James D. Winkler,Andrew P. Crew,Kevin Coleman,Craig M. Crews +10 more
TL;DR: ARV-825 is designed, a hetero-bifunctional PROTAC (Proteolysis Targeting Chimera) that recruits BRD4 to the E3 ubiquitin ligase cereblon, leading to fast, efficient, and prolonged degradation ofBRD4 in all BL cell lines tested.
Journal ArticleDOI
Proteasome inhibitors in cancer therapy
TL;DR: Investigation of the mechanisms of resistance is essential to further maximize the utility of this class of drugs in the era of personalized medicine.
Journal ArticleDOI
Selective Small Molecule Induced Degradation of the BET Bromodomain Protein BRD4
TL;DR: Proteolysis Targeted Chimeras (PROTACs) that tether JQ1 to a ligand for the E3 ubiquitin ligase VHL, aimed at triggering the intracellular destruction of BET proteins open up new opportunities to elucidate the cellular phenotypes and therapeutic implications associated with selective targeting of BRD4.
Journal ArticleDOI
Drug discovery in the ubiquitin–proteasome system
TL;DR: Recent advances linking UPS components with specific human diseases, most prominently cancer and neurodegenerative disorders, are reviewed and potential sites of therapeutic intervention along the regulated protein-degradation pathway are emphasized.
References
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Phosphorylation meets ubiquitination: the control of NF-[kappa]B activity.
Michael Karin,Yinon Ben-Neriah +1 more
TL;DR: Recent progress has been made in understanding the details of the signaling pathways that regulate NF-kappaB activity, particularly those responding to the proinflammatory cytokines tumor necrosis factor-alpha and interleukin-1.
Journal ArticleDOI
Activity of a Specific Inhibitor of the BCR-ABL Tyrosine Kinase in the Blast Crisis of Chronic Myeloid Leukemia and Acute Lymphoblastic Leukemia with the Philadelphia Chromosome
Brian J. Druker,Charles L. Sawyers,Hagop M. Kantarjian,Debra Resta,Sofia Fernandes Reese,John Ford,Renaud Capdeville,Moshe Talpaz +7 more
TL;DR: The BCR-ABL tyrosine kinase inhibitor STI571 is well tolerated and has substantial activity in the blast crises of CML and in Ph-positive ALL.
Journal ArticleDOI
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
TL;DR: 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.
Journal ArticleDOI
SCF and Cullin/RING H2-Based Ubiquitin Ligases
TL;DR: This review is focused on a conserved ubiquitin ligase complex known as SCF that plays a key role in marking a variety of regulatory proteins for destruction by the 26S proteasome.
Journal ArticleDOI
Role of Rpn11 Metalloprotease in Deubiquitination and Degradation by the 26S Proteasome
Rati Verma,L. Aravind,Robert S. Oania,W. Hayes McDonald,John R. Yates,Eugene V. Koonin,Raymond J. Deshaies +6 more
TL;DR: These findings reveal an unexpected coupling between substrate deubiquitination and degradation and suggest a unifying rationale for the presence of the lid in eukaryotic proteasomes.
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