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- Publisher Website: 10.1021/acschembio.8b01083
- Scopus: eid_2-s2.0-85066910039
- PMID: 31059647
- WOS: WOS:000497263200009
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Article: Covalent Ligand Screening Uncovers a RNF4 E3 Ligase Recruiter for Targeted Protein Degradation Applications
Title | Covalent Ligand Screening Uncovers a RNF4 E3 Ligase Recruiter for Targeted Protein Degradation Applications |
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Authors | |
Issue Date | 2019 |
Citation | ACS Chemical Biology, 2019, v. 14, n. 11, p. 2430-2440 How to Cite? |
Abstract | © 2019 American Chemical Society. Targeted protein degradation has arisen as a powerful strategy for drug discovery allowing the targeting of undruggable proteins for proteasomal degradation. This approach most often employs heterobifunctional degraders consisting of a protein-targeting ligand linked to an E3 ligase recruiter to ubiquitinate and mark proteins of interest for proteasomal degradation. One challenge with this approach, however, is that only a few E3 ligase recruiters currently exist for targeted protein degradation applications, despite the hundreds of known E3 ligases in the human genome. Here, we utilized activity-based protein profiling (ABPP)-based covalent ligand screening approaches to identify cysteine-reactive small-molecules that react with the E3 ubiquitin ligase RNF4 and provide chemical starting points for the design of RNF4-based degraders. The hit covalent ligand from this screen reacted with either of two zinc-coordinating cysteines in the RING domain, C132 and C135, with no effect on RNF4 activity. We further optimized the potency of this hit and incorporated this potential RNF4 recruiter into a bifunctional degrader linked to JQ1, an inhibitor of the BET family of bromodomain proteins. We demonstrate that the resulting compound CCW 28-3 is capable of degrading BRD4 in a proteasome- A nd RNF4-dependent manner. In this study, we have shown the feasibility of using chemoproteomics-enabled covalent ligand screening platforms to expand the scope of E3 ligase recruiters that can be exploited for targeted protein degradation applications. |
Persistent Identifier | http://hdl.handle.net/10722/282680 |
ISSN | 2023 Impact Factor: 3.5 2023 SCImago Journal Rankings: 1.344 |
ISI Accession Number ID |
DC Field | Value | Language |
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dc.contributor.author | Ward, Carl C. | - |
dc.contributor.author | Kleinman, Jordan I. | - |
dc.contributor.author | Brittain, Scott M. | - |
dc.contributor.author | Lee, Patrick S. | - |
dc.contributor.author | Chung, Clive Yik Sham | - |
dc.contributor.author | Kim, Kenneth | - |
dc.contributor.author | Petri, Yana | - |
dc.contributor.author | Thomas, Jason R. | - |
dc.contributor.author | Tallarico, John A. | - |
dc.contributor.author | McKenna, Jeffrey M. | - |
dc.contributor.author | Schirle, Markus | - |
dc.contributor.author | Nomura, Daniel K. | - |
dc.date.accessioned | 2020-05-28T01:57:10Z | - |
dc.date.available | 2020-05-28T01:57:10Z | - |
dc.date.issued | 2019 | - |
dc.identifier.citation | ACS Chemical Biology, 2019, v. 14, n. 11, p. 2430-2440 | - |
dc.identifier.issn | 1554-8929 | - |
dc.identifier.uri | http://hdl.handle.net/10722/282680 | - |
dc.description.abstract | © 2019 American Chemical Society. Targeted protein degradation has arisen as a powerful strategy for drug discovery allowing the targeting of undruggable proteins for proteasomal degradation. This approach most often employs heterobifunctional degraders consisting of a protein-targeting ligand linked to an E3 ligase recruiter to ubiquitinate and mark proteins of interest for proteasomal degradation. One challenge with this approach, however, is that only a few E3 ligase recruiters currently exist for targeted protein degradation applications, despite the hundreds of known E3 ligases in the human genome. Here, we utilized activity-based protein profiling (ABPP)-based covalent ligand screening approaches to identify cysteine-reactive small-molecules that react with the E3 ubiquitin ligase RNF4 and provide chemical starting points for the design of RNF4-based degraders. The hit covalent ligand from this screen reacted with either of two zinc-coordinating cysteines in the RING domain, C132 and C135, with no effect on RNF4 activity. We further optimized the potency of this hit and incorporated this potential RNF4 recruiter into a bifunctional degrader linked to JQ1, an inhibitor of the BET family of bromodomain proteins. We demonstrate that the resulting compound CCW 28-3 is capable of degrading BRD4 in a proteasome- A nd RNF4-dependent manner. In this study, we have shown the feasibility of using chemoproteomics-enabled covalent ligand screening platforms to expand the scope of E3 ligase recruiters that can be exploited for targeted protein degradation applications. | - |
dc.language | eng | - |
dc.relation.ispartof | ACS Chemical Biology | - |
dc.title | Covalent Ligand Screening Uncovers a RNF4 E3 Ligase Recruiter for Targeted Protein Degradation Applications | - |
dc.type | Article | - |
dc.description.nature | link_to_subscribed_fulltext | - |
dc.identifier.doi | 10.1021/acschembio.8b01083 | - |
dc.identifier.pmid | 31059647 | - |
dc.identifier.scopus | eid_2-s2.0-85066910039 | - |
dc.identifier.volume | 14 | - |
dc.identifier.issue | 11 | - |
dc.identifier.spage | 2430 | - |
dc.identifier.epage | 2440 | - |
dc.identifier.eissn | 1554-8937 | - |
dc.identifier.isi | WOS:000497263200009 | - |
dc.identifier.issnl | 1554-8929 | - |