A Method for Determining the Kinetics of Small-Molecule-Induced Ubiquitination
Recent advances in targeted protein degradation have enabled chemical hijacking of the ubiquitin–proteasome system to treat disease. The catalytic rate of cereblon (CRBN)-dependent bifunctional degradation activating compounds (BiDAC), which recruit CRBN to a chosen target protein, resulting in its...
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| Veröffentlicht in: | SLAS discovery 2021-04, Vol.26 (4), p.547-559 |
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| creator | Vieux, Ellen F. Agafonov, Roman V. Emerson, Lydia Isasa, Marta Deibler, Richard W. Simard, Jeffrey R. Cocozziello, David Ladd, Brendon Lee, Linda Li, Heng Archer, Stephen Fitzgerald, Mark Michael, Ryan Nasveschuk, Christopher G. Park, Eunice S. Kern, Gunther Proia, David A. Phillips, Andrew J. Fisher, Stewart L. |
| description | Recent advances in targeted protein degradation have enabled chemical hijacking of the ubiquitin–proteasome system to treat disease. The catalytic rate of cereblon (CRBN)-dependent bifunctional degradation activating compounds (BiDAC), which recruit CRBN to a chosen target protein, resulting in its ubiquitination and proteasomal degradation, is an important parameter to consider during the drug discovery process. In this work, an in vitro system was developed to measure the kinetics of BRD4 bromodomain 1 (BD1) ubiquitination by fitting an essential activator kinetic model to these data. The affinities between BiDACs, BD1, and CRBN in the binary complex, ternary complex, and full ubiquitination complex were characterized. Together, this work provides a new tool for understanding and optimizing the catalytic and thermodynamic properties of BiDACs. |
| doi_str_mv | 10.1177/24725552211000673 |
| format | Article |
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The catalytic rate of cereblon (CRBN)-dependent bifunctional degradation activating compounds (BiDAC), which recruit CRBN to a chosen target protein, resulting in its ubiquitination and proteasomal degradation, is an important parameter to consider during the drug discovery process. In this work, an in vitro system was developed to measure the kinetics of BRD4 bromodomain 1 (BD1) ubiquitination by fitting an essential activator kinetic model to these data. The affinities between BiDACs, BD1, and CRBN in the binary complex, ternary complex, and full ubiquitination complex were characterized. Together, this work provides a new tool for understanding and optimizing the catalytic and thermodynamic properties of BiDACs.</description><identifier>ISSN: 2472-5552</identifier><identifier>EISSN: 2472-5560</identifier><identifier>DOI: 10.1177/24725552211000673</identifier><identifier>PMID: 33780296</identifier><language>eng</language><publisher>Los Angeles, CA: Elsevier Inc</publisher><subject>Adaptor Proteins, Signal Transducing - genetics ; Adaptor Proteins, Signal Transducing - metabolism ; BiDAC ; Biological Assay ; Cell Cycle Proteins - chemistry ; Cell Cycle Proteins - genetics ; Cell Cycle Proteins - metabolism ; Cell-Free System - chemistry ; Cell-Free System - metabolism ; HeLa Cells ; Humans ; Kinetics ; Oxindoles - chemical synthesis ; Oxindoles - pharmacology ; Phthalimides - chemical synthesis ; Phthalimides - pharmacology ; Proteasome Endopeptidase Complex - drug effects ; Protein Binding ; Protein Domains ; Protein Processing, Post-Translational ; Proteolysis - drug effects ; targeted protein degradation ; Thermodynamics ; Transcription Factors - chemistry ; Transcription Factors - genetics ; Transcription Factors - metabolism ; Ubiquitin-Protein Ligases - genetics ; Ubiquitin-Protein Ligases - metabolism ; ubiquitination ; Ubiquitination - drug effects</subject><ispartof>SLAS discovery, 2021-04, Vol.26 (4), p.547-559</ispartof><rights>2021 Society for Laboratory Automation and Screening</rights><rights>The Author(s) 2021</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c435t-b57a019937a22b30687420dd2a70c81b0c5a437c6a8094c048efea787d88ec723</citedby><cites>FETCH-LOGICAL-c435t-b57a019937a22b30687420dd2a70c81b0c5a437c6a8094c048efea787d88ec723</cites><orcidid>0000-0003-3815-4366</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33780296$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Vieux, Ellen F.</creatorcontrib><creatorcontrib>Agafonov, Roman V.</creatorcontrib><creatorcontrib>Emerson, Lydia</creatorcontrib><creatorcontrib>Isasa, Marta</creatorcontrib><creatorcontrib>Deibler, Richard W.</creatorcontrib><creatorcontrib>Simard, Jeffrey R.</creatorcontrib><creatorcontrib>Cocozziello, David</creatorcontrib><creatorcontrib>Ladd, Brendon</creatorcontrib><creatorcontrib>Lee, Linda</creatorcontrib><creatorcontrib>Li, Heng</creatorcontrib><creatorcontrib>Archer, Stephen</creatorcontrib><creatorcontrib>Fitzgerald, Mark</creatorcontrib><creatorcontrib>Michael, Ryan</creatorcontrib><creatorcontrib>Nasveschuk, Christopher G.</creatorcontrib><creatorcontrib>Park, Eunice S.</creatorcontrib><creatorcontrib>Kern, Gunther</creatorcontrib><creatorcontrib>Proia, David A.</creatorcontrib><creatorcontrib>Phillips, Andrew J.</creatorcontrib><creatorcontrib>Fisher, Stewart L.</creatorcontrib><title>A Method for Determining the Kinetics of Small-Molecule-Induced Ubiquitination</title><title>SLAS discovery</title><addtitle>J Biomol Screen</addtitle><description>Recent advances in targeted protein degradation have enabled chemical hijacking of the ubiquitin–proteasome system to treat disease. The catalytic rate of cereblon (CRBN)-dependent bifunctional degradation activating compounds (BiDAC), which recruit CRBN to a chosen target protein, resulting in its ubiquitination and proteasomal degradation, is an important parameter to consider during the drug discovery process. In this work, an in vitro system was developed to measure the kinetics of BRD4 bromodomain 1 (BD1) ubiquitination by fitting an essential activator kinetic model to these data. The affinities between BiDACs, BD1, and CRBN in the binary complex, ternary complex, and full ubiquitination complex were characterized. 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Agafonov, Roman V. ; Emerson, Lydia ; Isasa, Marta ; Deibler, Richard W. ; Simard, Jeffrey R. ; Cocozziello, David ; Ladd, Brendon ; Lee, Linda ; Li, Heng ; Archer, Stephen ; Fitzgerald, Mark ; Michael, Ryan ; Nasveschuk, Christopher G. ; Park, Eunice S. ; Kern, Gunther ; Proia, David A. ; Phillips, Andrew J. ; Fisher, Stewart L.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c435t-b57a019937a22b30687420dd2a70c81b0c5a437c6a8094c048efea787d88ec723</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Adaptor Proteins, Signal Transducing - genetics</topic><topic>Adaptor Proteins, Signal Transducing - metabolism</topic><topic>BiDAC</topic><topic>Biological Assay</topic><topic>Cell Cycle Proteins - chemistry</topic><topic>Cell Cycle Proteins - genetics</topic><topic>Cell Cycle Proteins - metabolism</topic><topic>Cell-Free System - chemistry</topic><topic>Cell-Free System - metabolism</topic><topic>HeLa Cells</topic><topic>Humans</topic><topic>Kinetics</topic><topic>Oxindoles - chemical synthesis</topic><topic>Oxindoles - pharmacology</topic><topic>Phthalimides - chemical synthesis</topic><topic>Phthalimides - pharmacology</topic><topic>Proteasome Endopeptidase Complex - drug effects</topic><topic>Protein Binding</topic><topic>Protein Domains</topic><topic>Protein Processing, Post-Translational</topic><topic>Proteolysis - drug effects</topic><topic>targeted protein degradation</topic><topic>Thermodynamics</topic><topic>Transcription Factors - chemistry</topic><topic>Transcription Factors - genetics</topic><topic>Transcription Factors - metabolism</topic><topic>Ubiquitin-Protein Ligases - genetics</topic><topic>Ubiquitin-Protein Ligases - metabolism</topic><topic>ubiquitination</topic><topic>Ubiquitination - drug effects</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Vieux, Ellen F.</creatorcontrib><creatorcontrib>Agafonov, Roman V.</creatorcontrib><creatorcontrib>Emerson, Lydia</creatorcontrib><creatorcontrib>Isasa, Marta</creatorcontrib><creatorcontrib>Deibler, Richard W.</creatorcontrib><creatorcontrib>Simard, Jeffrey R.</creatorcontrib><creatorcontrib>Cocozziello, David</creatorcontrib><creatorcontrib>Ladd, Brendon</creatorcontrib><creatorcontrib>Lee, Linda</creatorcontrib><creatorcontrib>Li, Heng</creatorcontrib><creatorcontrib>Archer, Stephen</creatorcontrib><creatorcontrib>Fitzgerald, Mark</creatorcontrib><creatorcontrib>Michael, Ryan</creatorcontrib><creatorcontrib>Nasveschuk, Christopher G.</creatorcontrib><creatorcontrib>Park, Eunice S.</creatorcontrib><creatorcontrib>Kern, Gunther</creatorcontrib><creatorcontrib>Proia, David A.</creatorcontrib><creatorcontrib>Phillips, Andrew J.</creatorcontrib><creatorcontrib>Fisher, Stewart L.</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Sage Journals GOLD Open Access 2024</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>SLAS discovery</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Vieux, Ellen F.</au><au>Agafonov, Roman V.</au><au>Emerson, Lydia</au><au>Isasa, Marta</au><au>Deibler, Richard W.</au><au>Simard, Jeffrey R.</au><au>Cocozziello, David</au><au>Ladd, Brendon</au><au>Lee, Linda</au><au>Li, Heng</au><au>Archer, Stephen</au><au>Fitzgerald, Mark</au><au>Michael, Ryan</au><au>Nasveschuk, Christopher G.</au><au>Park, Eunice S.</au><au>Kern, Gunther</au><au>Proia, David A.</au><au>Phillips, Andrew J.</au><au>Fisher, Stewart L.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A Method for Determining the Kinetics of Small-Molecule-Induced Ubiquitination</atitle><jtitle>SLAS discovery</jtitle><addtitle>J Biomol Screen</addtitle><date>2021-04</date><risdate>2021</risdate><volume>26</volume><issue>4</issue><spage>547</spage><epage>559</epage><pages>547-559</pages><issn>2472-5552</issn><eissn>2472-5560</eissn><abstract>Recent advances in targeted protein degradation have enabled chemical hijacking of the ubiquitin–proteasome system to treat disease. 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| subjects | Adaptor Proteins, Signal Transducing - genetics Adaptor Proteins, Signal Transducing - metabolism BiDAC Biological Assay Cell Cycle Proteins - chemistry Cell Cycle Proteins - genetics Cell Cycle Proteins - metabolism Cell-Free System - chemistry Cell-Free System - metabolism HeLa Cells Humans Kinetics Oxindoles - chemical synthesis Oxindoles - pharmacology Phthalimides - chemical synthesis Phthalimides - pharmacology Proteasome Endopeptidase Complex - drug effects Protein Binding Protein Domains Protein Processing, Post-Translational Proteolysis - drug effects targeted protein degradation Thermodynamics Transcription Factors - chemistry Transcription Factors - genetics Transcription Factors - metabolism Ubiquitin-Protein Ligases - genetics Ubiquitin-Protein Ligases - metabolism ubiquitination Ubiquitination - drug effects |
| title | A Method for Determining the Kinetics of Small-Molecule-Induced Ubiquitination |
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